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Chitayat-Hall and Schaaf-Yang syndromes: a common aetiology: expanding the phenotype of MAGEL2 -related disorders

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Background Chitayat-Hall syndrome, initially described in 1990, is a rare condition characterised by distal arthrogryposis, intellectual disability, dysmorphic features and hypopituitarism, in particular growth hormone deficiency. The genetic aetiology has not been identified. Methods and results We identified three unrelated families with a total of six affected patients with the clinical manifestations of Chitayat-Hall syndrome. Through whole exome or whole genome sequencing, pathogenic variants in the MAGEL2 gene were identified in all affected patients. All disease-causing sequence variants detected are predicted to result in a truncated protein, including one complex variant that comprised a deletion and inversion. Conclusions Chitayat-Hall syndrome is caused by pathogenic variants in MAGEL2 and shares a common aetiology with the recently described Schaaf-Yang syndrome. The phenotype of MAGEL2-related disorders is expanded to include growth hormone deficiency as an important and treatable complication.
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316 JoblingR, etal. J Med Genet 2018;55:316–321. doi:10.1136/jmedgenet-2017-105222
SHORT REPORT
Chitayat-Hall and Schaaf-Yang syndromes:
a common aetiology: expanding the phenotype of
MAGEL2-relateddisorders
Rebekah Jobling,1,2 Dimitri James Stavropoulos,1,3 Christian R Marshall,1,4
Cheryl Cytrynbaum,2 Michelle M Axford,1 Vanessa Londero,1 Sharon Moalem,5
Jennifer Orr,1 Francis Rossignol,6,7 Fatima Daniela Lopes,6,8,9 Julie Gauthier,6
Nathalie Alos,6,7 Rosemarie Rupps,10 Margaret McKinnon,10 Shelin Adam,10
Malgorzata J M Nowaczyk,11 Susan Walker,4,12 Stephen W Scherer,4,12,13
Christina Nassif,6,7 Fadi F Hamdan,6,7 Cheri L Deal,6,7 Jean-François Soucy,6,7
Rosanna Weksberg,2 Patrick Macleod,14 Jacques L Michaud,6,7 David Chitayat2,15
Phenotypes
To cite: JoblingR,
StavropoulosDJ, MarshallCR,
etal. J Med Genet
2018;55:316–321.
Additional material is
published online only. To view
please visit the journal online
(http:// dx. doi. org/ 10. 1136/
jmedgenet- 2017- 105222).
For numbered affiliations see
end of article.
Correspondence to
Dr David Chitayat, Division
of Clinical Genetics and
Metabolism, Department of
Pediatrics, The Hospital for Sick
Children, Toronto, ON M5G
1X8, Canada; David. Chitayat@
sinaihealthsystem. ca
JLM and DC contributed equally.
Received 16 December 2017
Revised 2 March 2018
Accepted 11 March 2018
Published Online First
29March2018
ABSTRACT
Background Chitayat-Hall syndrome, initially described
in 1990, is a rare condition characterised by distal
arthrogryposis, intellectual disability, dysmorphic features
and hypopituitarism, in particular growth hormone
deficiency. The genetic aetiology has not been identified.
Methods and results We identified three unrelated
families with a total of six affected patients with the
clinical manifestations of Chitayat-Hall syndrome.
Through whole exome or whole genome sequencing,
pathogenic variants in the MAGEL2 gene were identified
in all affected patients. All disease-causing sequence
variants detected are predicted to result in a truncated
protein, including one complex variant that comprised a
deletion and inversion.
Conclusions Chitayat-Hall syndrome is caused by
pathogenic variants in MAGEL2 and shares a common
aetiology with the recently described Schaaf-Yang
syndrome. The phenotype of MAGEL2-related disorders
is expanded to include growth hormone deficiency as an
important and treatable complication.
INTRODUCTION
In 1990 Chitayat et al1 reported siblings with
distal arthrogryposis, hypopituitarism, intellec-
tual disability and dysmorphisms. This condition
is known as Chitayat-Hall syndrome or distal
arthrogryposis with hypopituitarism including
growth hormone (GH) deficiency, mental retar-
dation and facial anomalies (OMIM #208080).
A similar phenotype has been described in other
patients, including one case with consanguineous
parents. Autosomal recessive inheritance has been
suggested based on the history of consanguinity and
sibling recurrence.1–3 Here we report six patients
with Chitayat-Hall syndrome from four fami-
lies, including updated information on the female
proband originally reported by Chitayat et al.1 All
patients were found to have truncating sequence
variants in the MAGEL2 gene, including the first
reported disease-causing complex rearrangement
involving MAGEL2. Patients with truncating
variants in MAGEL2 have been described to
have Schaaf-Yang syndrome (SHFYNG; OMIM
#615547), a variable phenotype characterised
by intellectual disability, early feeding difficulties
followed by excessive weight gain in some patients,
hypotonia, and contractures ranging in severity
from distal arthrogryposis to severe arthrogryp-
osis multiplex congenita.4–6 We demonstrate that
Chitayat-Hall syndrome has the same aetiology as
SHFYNG, and that GH deficiency is an important
feature of this condition.
CLINICAL REPORTS
The cohort was recruited from centres across
Canada. All patients initially received a clin-
ical diagnosis of Chitayat-Hall syndrome from a
medical geneticist, with the exception of patient
4-I, who did not have a clinical diagnosis but was
noted to have similar features. Clinical features
are summarised in table 1. Pedigrees are shown in
figure 1 and patient photographs in figure 2. Full
phenotype reports are found in the online supple-
mentary clinical information. Here we provide
detailed information regarding GH deficiency in
this cohort. Consent to publish clinical information
was obtained from all families.
Patient 1-I presented with poor growth velocity.
She was treated with somatotropin until age 17.
Her final height is on the 10th percentile. In addi-
tion to GH deficiency, she has central hypothy-
roidism and is treated with levothyroxine.1 She has
not been formally investigated for hypogonadism,
but has amenorrhoea.
At 4 months of age patient 2-I presented with
rhythmic limb movements. At arrival to the emer-
gency room, blood glucose was 2.2 mmol/L. She
suffered recurrent hypoglycaemic episodes, with
critical samples taken on three occasions and
showing low GH levels: 1.04 μg/L, 0.8 μg/L and
2.45 μg/L with blood glucose concentrations of
1.3 mmol/L, 0.8 mmol/L and 2.3 mmol/L, respec-
tively. She was started on somatotropin treat-
ment at 0.17 mg/kg/week and the hypoglycaemic
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Phenotypes
episodes decreased. She presented again at 11 months with a
further episode of hypoglycaemia. Arginine stimulation testing
confirmed GH deficiency with a peak GH level of 1.32 μg/L.
Her somatotropin dose was adjusted to 0.18 mg/kg/week and
her glycaemic control improved again. At age 2, a brain MRI
revealed hypothalamic hypoplasia, with normal sella turcica.
Her height increased from the 5th to the 25th percentile after
treatment.
Her younger sister, patient 2-II, presented at 2 months with
multiple hypoglycaemic episodes, including during an arginine
stimulation test. GH was inappropriately low on multiple crit-
ical samples: 4.8 μg/L, 4.6 μg/L and 3.3 μg/L with blood glucose
concentrations of 2.2 mmol/L, 2.8 mmol/L and 1.8 mmol/L,
respectively. The rest of the endocrine and metabolic work-up
was normal. She was treated with somatotropin at 0.23 mg/kg/
week, since her hypoglycaemia was more severe. Subsequently
the dose was reduced to 0.185 mg/kg/week. After treatment
her height increased from below the 3rd to the 25th percentile.
Brain MRI at age 6 showed hypersignal of the pituitary stalk and
posterior pituitary.
Patient 3-II developed seizures at 12 months, thought to have
been precipitated by hypoglycaemia (glucose 2.4 mmol/L). At
14 months of age her Insulin-like growth factor 1 (IGF-1) was
27 μg/L (reference value 49–342 μg/L). Arginine stimulation
testing revealed GH deficiency (GH peak value 4.1 μg/L). Her
blood glucose was monitored leading to a decision not to start
somatotropin treatment. At 3 years of age she presented again
with hypoglycaemic seizures. A critical sample showed an
insulin level of 26 pmol/L, GH was low at 0.08 μg/L, beta-hy-
droxybutyrate was 0.020 mmol/L (normal, 0.02–0.29 mmol/L)
and free fatty acids was 263 µmol/L (normal, 100–900 µmol/L)
for a glucose of 1.7 mmol/L. However, a second critical sample
showed a fully suppressed insulin of <7 pmol/L and GH of 0.2
μg/L, for a glucose of 2.5 mmol/L. Her blood glucose was moni-
tored regularly and the hypoglycaemic episodes have improved
over time. She has not been treated with somatotropin.
Table 1 Clinical features of patients with Chitayat-Hall syndrome
Patient 1-I 2-I 2-II 3-I 3-II 4-I
Literature*
(affected
(n)/with
information
available (n))
Variant Partial deletion/
inversion
c.1762 C>T
(p.Gln588Ter)
c.1762 C>T
(p.Gln588Ter)
c.2179_2180del
(p.Asp727Profs*6)
c.2179_2180del
(p.Asp727Profs*6)
c.1996dupC
(p.Gln666Profs*47)
Age at last assessment
(years)
35 13 11 10 8 6
Short stature + + + + + + 14/22
Increased
subcutaneous fat
Noted in infancy,
current BMI 19.4
NR NR + + + 9/20
Developmental delay/
intellectual disability
+ (moderate) + + + (severe) + (severe) + (severe) 22/22
Eye abnormalities + (nystagmus,
microcornea,
glaucoma)
+ (nystagmus,
microcornea)
+ (myopia, hyperopia,
exotropia)
16/20†
Dysmorphisms + + + + + + 25/30
Heart defect + (patent foramen
ovale)
+(atrial septal defect) NR
Feeding problems + + + + 22/24
Gastro-oesophageal
reflux
+ + + + 8/14
Contractures + + + + + + 25/30
Scoliosis/kyphosis + + + + + + 9/19
Hypoglycaemic
episodes
+ + + + + 3/3‡
Growth hormone
deficiency
+ + + + + + 1/1§
Hypothyroidism + NR
Hypotonia + + + + + + 15/15
MRI abnormalities MRI not
performed
Early myelination
delay,
hypothalamic
hypoplasia
Hypersignal of
pituitary stalk
Frontal volume loss and
decreased pituitary size
MRI not performed Thin pituitary stalk,
dilatation of third
ventricle possibly due to
hypothalamic atrophy,
ventriculomegaly
Previous normal
genetic testing
Karyotype,
array genomic
hybridisation
Karyotype, fragile
X,
Array genomic
hybridisation,
fragile X
Karyotype, array
genomic hybridisation
Array genomic
hybridisation
Karyotype, array genomic
hybridisation
NR indicates that this information was not reported.
*Refs 4–6, 10–12.
†Esotropia, myopia and strabismus.
‡Hyperinsulinaemic hypoglycaemia10 and recurrent hypoglycaemia of unknown origin.11
§Ref4.
BMI, body mass index.
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318 JoblingR, etal. J Med Genet 2018;55:316–321. doi:10.1136/jmedgenet-2017-105222
Phenotypes
Following the diagnosis of GH deficiency in her younger sister,
patient 3-I was investigated. Her IGF-1 was low at <25 μg/L at
3 years and 10 months and 28 μg/L at 6 years 1 month (reference
value 49–342 μg/L). Arginine stimulation testing revealed a peak
value of 2.7 μg/L. Her blood glucose was monitored, but the
decision was made not to start somatotropin treatment. Brain
MRI at 4 years showed a small pituitary gland.
Patient 4-I had hypoglycaemic episodes requiring hospitalisa-
tion at 6 months. GH deficiency was first suspected at 11 months
and confirmed at 19 months. The GH measured during two
hypoglycaemic episodes was low and a clonidine GH stimula-
tion test showed a deficiency (GH peak value 4.42 μg/L). The
arginine GH stimulation test was also abnormal (4.435 mg intra-
venously ×1: GH peak value 3.53 μg/L). She was successfully
treated with somatotropin. With treatment her height increased
from below the 3rd to the 10th percentile. Brain MRI done at
3 months and repeated at 3 years and 7 months revealed a thin
pituitary stalk and slight dilation of the third ventricle, possibly
secondary to hypothalamic atrophy.
Detailed results of GH stimulation testing can be found in
online supplementary clinical information, tables 1–3.
METHODS
For all families, genetic analysis was performed by either whole
genome sequencing (WGS) or whole exome sequencing (WES)
with pathogenic variants confirmed by Sanger sequencing. For
family 1, WGS of the proband and her father was performed.
WES was performed on samples from affected patients in family
2, and the probands in families 3 and 4 (online supplementary
methods).
Analysis of WES and WGS data prioritised variants based on
allele frequency, presence in databases of medically relevant vari-
ants including ClinVar7 and the Human Gene Mutation Data-
base,8 predicted impact on coding sequence, phenotype in the
OMIM database, zygosity, and mode of inheritance. In family 2,
where both affected individuals were sequenced, shared variants
were examined. In family 1 variants shared between the proband
and her unaffected father were prioritised due to the paternal
family history of similarly affected individuals (figure 1, online
supplementary figure 5).
Since MAGEL2 is expressed exclusively from the paternal
allele, only pathogenic variants located on the paternal allele
will cause disease.9 To determine the parental origin of the
c.2179_2180del variant identified in family 3, long-range PCR
of MAGEL2 followed by Sanger sequencing was performed on
genomic DNA after methylation-sensitive digestion, as described
previously4 (online supplementary methods).
SEQUENCING RESULTS
All affected individuals were found to carry truncating variants
in MAGEL2. Patient 1-I was found to have a complex rear-
rangement interrupting the MAGEL2 gene, consisting of a 22 kb
inversion and 3 kb deletion that removes the last 852 bp and
the 3’ end of the gene (online supplementary figures 1–3). The
variant was paternally inherited and segregation analysis for
several additional family members was performed (figure 1).
Siblings 2-I and 2-II have a nonsense variant (NM_019066;
c.1762 C>T(p.Gln588Ter)) in MAGEL2. Parental samples were
not available for testing. Patients 3-I and 3-II carry a frameshift
variant (c.2179_2180del(p.Asp727Profs*6)) in MAGEL2. The
Figure 1 Pedigrees and MAGEL2 variants identified in patients with Chitayat-Hall syndrome. Filled black squares and circles indicate clinically affected
individuals, black dots indicate carriers, V indicates that the familial variant was found in an individual,+indicates the reference sequence and NT indicates
that the individual was not tested.
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Phenotypes
variant was not present in parents or unaffected siblings, and was
determined to be on the paternal allele (online supplementary
figure 4). Patient 4-I has a previously reported frameshift inser-
tion (c.1996dupC(p.Gln666Profs*47))6 in MAGEL2, inherited
from her unaffected father.
DISCUSSION
Multiple features first reported in Chitayat-Hall syndrome
overlap with those described in the majority of individuals with
SHFYNG, including contractures, hypotonia, developmental
delay/intellectual disability, feeding difficulties, dysmorphisms,
small hands and feet, and tapering fingers.1 4–6 10–12 Our cohort
also has other features reported in a minority of individuals,
including scoliosis, gastro-oesophageal reflux, increased subcu-
taneous fat and prominent ridge over the metopic suture. While
eye abnormalities are described, this is the first report of micro-
cornea in patients with an MAGEL2-related disorder.6
The most common pathogenic sequence variant identified to
date in MAGEL2, c.1996dupC(p.Gln666Profs*47), has been
reported in 14 individuals from nine families diagnosed with
SHFYNG.6 10 11 These individuals present with the features most
commonly described in association with SHFYNG, including
contractures, developmental delay/intellectual disability, dysmor-
phism, hypotonia and feeding difficulties. Short stature was
reported in 6/14 cases. Our patient 4-I, with the c.1996dupC
variant, has a very similar phenotype to the 14 reported patients,
apart from her GH deficiency. Unfortunately, there is no infor-
mation available regarding GH levels in these 14 individuals.
Deficiency of hormones produced by the anterior pituitary
is a prominent feature of Chitayat-Hall syndrome. All patients
reported here demonstrated biochemical abnormalities related
to GH deficiency on more than one occasion, with either low
IGF-1, low GH peak after arginine stimulation, low GH in the
context of hypoglycaemia, or all of the above. One patient with
SHFYNG has been previously reported to have GH deficiency,
presenting with poor linear growth and treated from 2 years of
age.4 However, short stature is common in these patients, and is
likely caused by undiagnosed GH deficiency in some cases.4 6 11
Four patients in our study presented with hypoglycaemia, another
manifestation of GH deficiency. Hypoglycaemic episodes have
not been reported in the majority of patients with SHFYNG,
although may go undiagnosed if not leading to convulsions or
loss of consciousness.
The pathophysiology of GH deficiency in patients with
MAGEL2 variants requires further investigation. MRI findings
in our patients were not consistent, although it is notable that
imaging for patients 2-I and 4-I demonstrated possible hypotha-
lamic hypoplasia. Magel2 is expressed in both fetal and adult
brain,9 13 and mouse studies have demonstrated robust expres-
sion in the fetal hypothalamus. In adult mice Magel2 is mainly
Figure 2 Features of affected patients. (A) Patient I-1—myopathic faces with droopy eyelids and open mouth. (B,C) Patients 2-I and 2-II, respectively—
both sisters had minor facial dysmorphism with a high forehead, a flat forehead in patient 2-I (B) and frontal bossing in patient 2-II (C) with a ridge over
the metopic suture, deep set eyes, depressed nasal bridge with a broad nasal root and tip, and a ‘square’ chin with a horizontal groove over the chin. In
patient 2-II (C) note thelow-set ears with the right ear being lower than the left. (D) Patient 3-I—high forehead with a ridge over the metopic suture,
hypoplastic supraorbital ridges, deep set eyes, a broad nasal root and tip and a long philtrum, full cheeks, thin upper lip and retrognathia with a square
chin and a horizontal groove over the chin. (E) Hand of patient 3-II—‘Puffy’ hand with proximally inserted thumb, tapering fingers and camptodactyly with
absent distal flexion creases. (F) Patient 3-II—deep set eyes, a broad nasal root and tip, long philtrum, thin upper lip, retrognathia, a ‘square’ chin with a
horizontal groove over the chin and low-set ears. (G) Patient 4-I—ridge over the metopic suture, deep set eyes, a broad nasal root and tip, thin upper lip,
retrognathia with a square chin, a horizontal groove over the chin and low-set ears. (H) Hand of patient 4-I—adducted thumb with the second and fifth
fingers overlapping the third and fourth.
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Phenotypes
expressed in the hypothalamus, including the arcuate nucleus
where GH-releasing hormone (GHRH) is produced.14 15 There
is evidence of GH deficiency related to hypothalamic dysfunc-
tion in the Magel2-null mouse. Tennese and Wevrick16 found
low levels of IGF-1 in female Magel2-null mice compared with
controls. The mice demonstrated a blunted response to hypo-
thalamic stimulation of the GH pathway with ghrelin compared
with wild-type littermates, while their response to GHRH was
equivalent, indicating a possible hypothalamic origin for the
deficiency.16
Family 1 carries a complex rearrangement and partial
deletion. To our knowledge this is the first report of such a
change causing an MAGEL2-related disorder. The first 2.9 kb
of the coding and the 5’ region are apparently intact, and it
is possible that a truncated protein product is produced. It
has been suggested that frameshift and nonsense variants in
MAGEL2 escape nonsense-mediated decay and have a neomor-
phic or dominant negative effect, explaining the milder pheno-
type seen in full gene deletions.6 17 18 Functional studies are
required to investigate this possibility, but are difficult to
pursue given that the expression of MAGEL2 in adult tissues
is very limited.9 13 This case illustrates the benefits of WGS
as a diagnostic test, as this complex variant would not have
been detected using exome, microarray or targeted sequencing
methodologies.
In family 3 we demonstrated that the variant identified in
the two affected sisters was on the paternal allele. It was not
detectable in paternal blood by Sanger sequencing. This does
not rule out the possibility of low level mosaicism in blood or
other tissues. This is the third reported case of apparent mosa-
icism in an unaffected father in MAGEL2-related disorder.10 11
In this situation, the recurrence risk could be up to 50%.
The phenotype of MAGEL2-related disorder continues to
evolve, now including Chitayat-Hall syndrome. With the excep-
tion of the endocrinological findings we describe, our patients’
phenotypes are very similar to those observed in patients with
SHFYNG, and one of our patients carries the most common
recurrent variant c.1996dupC reported in SHFYNG. This
suggests that SHFYNG and Chitayat-Hall syndromes are likely
the same disorder. A systematic investigation of endocrinolog-
ical abnormalities in patients with MAGEL2-related disorder is
needed and GH deficiency should always be considered in the
context of poor growth and/or hypoglycaemia.
Author affiliations
1Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital
for Sick Children, Toronto, Ontario, Canada
2Division of Clinical Genetics and Metabolism, Department of Pediatrics, The Hospital
for Sick Children, Toronto, Ontario, Canada
3Department of Laboratory Medicine and Pathobiology, University of Toronto,
Toronto, Ontario, Canada
4The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario,
Canada
5Regenoron, New York City, New York, USA
6CHU Sainte-Justine, Montréal, Quebec, Canada
7Department of Pediatrics, Université de Montréal, Montréal, Quebec, Canada
8Life and Health Sciences Research Institute (ICVS), School of Medicine, University of
Minho, Braga, Portugal
9ICVS/3B’s - PT Government Associate Laboratory, Guimarães, Portugal
10Department of Medical Genetics, University of British Columbia, Vancouver, British
Columbia, Canada
11Division of Clinical Pathology, McMaster University, Hamilton, Ontario, Canada
12Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto,
Ontario, Canada
13Department of Molecular Genetics and McLaughlin Centre, University of Toronto,
Toronto, Ontario, Canada
14The Centre for Biomedical Research, University of Victoria, Victoria, British
Columbia, Canada
15The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics
and Gynecology, Mount Sinai Hospital, New York City, New York, USA
Acknowledgements We would like to thank the families who participated in
this work. The authors also thank, the SickKids Centre for Genetic Medicine, the
University of Toronto McLaughlin Centre, The Toronto Centre for Applied Genomics,
and the GlaxoSmithKline-CIHR Chair in Genome Sciences at The Hospital for Sick
Children and the University of Toronto (SWS), and the Fondation Jeanne et Jean-
Louis Lévesque (JLM).
Contributors CC, SM, FR, NA, RR, MM, SA, MJMN, CLD, RW, PM and DC
performed clinical assessment and provided phenotypic information regarding the
patients. FR, FDL, JG, FFH, CN, J-FS, JLM, RJ, DJS, CRM, SWS, JO and SW provided
sequencing, data analysis, interpretation and validation of variants. RJ, VL and
MMA performed phasing experiments for the variant in family 3. The manuscript
was drafted by RJ, FR, DC and JLM. All authors provided critical revision of the
article.
Funding The McLaughlin Centre, University of Toronto, Toronto, Canada, and
Fondation Jeanne et Jean- Louis Lévesque (JLM). The Centre for Genetic Medicine,
The Hospital for Sick Children, Toronto, Canada. FDL has a fellowship funded by FCT
- Fundação para a Ciência e a Tecnologia (SFRH/BD/84650/2010).
Competing interests None declared.
Patient consent Parental/guardian consent obtained.
Ethics approval The Hospital for Sick Children, Toronto, Canada, and Centre
hospitalier universitaire Sainte-Justine.
Provenance and peer review Not commissioned; externally peer reviewed.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2018. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
REFERENCES
1 Chitayat D, Hall JG, Couch RM, Phang MS, Baldwin VJ. Syndrome of mental
retardation, facial anomalies, hypopituitarism, and distal arthrogryposis in sibs. Am J
Med Genet 1990;37:65–70.
2 Smigiel R, Basiak A, Misiak B, Pesz K. Panhypopituitary insufficiency in a patient with
clinical diagnosis of Chitayat-Hall syndrome. Endokrynol Pol 2010;61:318–21.
3 Rao V, El-Alem T, Aminu K, Mankad K, Cowan F, Holder SE, Kinali M. Chitayat-Hall
syndrome: extending the clinical phenotype. Clin Dysmorphol 2013;22:156–60.
4 Schaaf CP, Gonzalez-Garay ML, Xia F, Potocki L, Gripp KW, Zhang B, Peters BA,
McElwain MA, Drmanac R, Beaudet AL, Caskey CT, Yang Y. Truncating mutations of
MAGEL2 cause Prader-Willi phenotypes and autism. Nat Genet 2013;45:1405–8.
5 Mejlachowicz D, Nolent F, Maluenda J, Ranjatoelina-Randrianaivo H, Giuliano F, Gut I,
Sternberg D, Laquerrière A, Melki J. Truncating Mutations of MAGEL2, a Gene within
the Prader-Willi Locus, Are Responsible for Severe Arthrogryposis. Am J Hum Genet
2015;97:616–20.
6 Fountain MD, Aten E, Cho MT, Juusola J, Walkiewicz MA, Ray JW, Xia F, Yang Y,
Graham BH, Bacino CA, Potocki L, van Haeringen A, Ruivenkamp CA, Mancias P,
Northrup H, Kukolich MK, Weiss MM, van Ravenswaaij-Arts CM, Mathijssen IB,
Levesque S, Meeks N, Rosenfeld JA, Lemke D, Hamosh A, Lewis SK, Race S, Stewart
LL, Hay B, Lewis AM, Guerreiro RL, Bras JT, Martins MP, Derksen-Lubsen G, Peeters
E, Stumpel C, Stegmann S, Bok LA, Santen GW, Schaaf CP. The phenotypic spectrum
of Schaaf-Yang syndrome: 18 new affected individuals from 14 families. Genet Med
2017;19:45–52.
7 Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, Gu B, Hart J,
Hoffman D, Hoover J, Jang W, Katz K, Ovetsky M, Riley G, Sethi A, Tully R, Villamarin-
Salomon R, Rubinstein W, Maglott DR. ClinVar: public archive of interpretations of
clinically relevant variants. Nucleic Acids Res 2016;44(D1):D862–8.
8 Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips
AD, Cooper DN. The Human Gene Mutation Database: towards a comprehensive
repository of inherited mutation data for medical research, genetic diagnosis and
next-generation sequencing studies. Hum Genet 2017;136:665–77.
9 Boccaccio I, Glatt-Deeley H, Watrin F, Roëckel N, Lalande M, Muscatelli F. The human
MAGEL2 gene and its mouse homologue are paternally expressed and mapped to the
Prader-Willi region. Hum Mol Genet 1999;8:2497–505.
10 Soden SE, Saunders CJ, Willig LK, Farrow EG, Smith LD, Petrikin JE, LePichon JB, Miller
NA, Thiffault I, Dinwiddie DL, Twist G, Noll A, Heese BA, Zellmer L, Atherton AM,
Abdelmoity AT, Safina N, Nyp SS, Zuccarelli B, Larson IA, Modrcin A, Herd S, Creed
M, Ye Z, Yuan X, Brodsky RA, Kingsmore SF. Effectiveness of exome and genome
sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders.
Sci Transl Med 2014;6:265ra168.
11 Palomares-Bralo M, Vallespín E, Del Pozo Á, Ibañez K, Silla JC, Galán E, Gordo G,
Martínez-Glez V, Alba-Valdivia LI, Heath KE, García-Miñaúr S, Lapunzina P, Santos-
Simarro F. Pitfalls of trio-based exome sequencing: imprinted genes and parental
mosaicism-MAGEL2 as an example. Genet Med 2017;19:1285–6.
on 10 August 2018 by guest. Protected by copyright.http://jmg.bmj.com/J Med Genet: first published as 10.1136/jmedgenet-2017-105222 on 29 March 2018. Downloaded from
321
JoblingR, etal. J Med Genet 2018;55:316–321. doi:10.1136/jmedgenet-2017-105222
Phenotypes
12 Urreizti R, Cueto-Gonzalez AM, Franco-Valls H, Mort-Farre S, Roca-Ayats N,
Ponomarenko J, Cozzuto L, Company C, Bosio M, Ossowski S, Montfort M, Hecht J,
Tizzano EF, Cormand B, Vilageliu L, Opitz JM, Neri G, Grinberg D, Balcells S. A De Novo
Nonsense Mutation in MAGEL2 in a Patient Initially Diagnosed as Opitz-C: Similarities
Between Schaaf-Yang and Opitz-C Syndromes. Sci Rep 2017;7:44138.
13 Lee S, Kozlov S, Hernandez L, Chamberlain SJ, Brannan CI, Stewart CL, Wevrick R.
Expression and imprinting of MAGEL2 suggest a role in Prader-willi syndrome and the
homologous murine imprinting phenotype. Hum Mol Genet 2000;9:1813–9.
14 Kozlov SV, Bogenpohl JW, Howell MP, Wevrick R, Panda S, Hogenesch JB, Muglia LJ,
Van Gelder RN, Herzog ED, Stewart CL. The imprinted gene Magel2 regulates normal
circadian output. Nat Genet 2007;39:1266–72.
15 Maillard J, Park S, Croizier S, Vanacker C, Cook JH, Prevot V, Tauber M, Bouret SG. Loss
of Magel2 impairs the development of hypothalamic Anorexigenic circuits. Hum Mol
Genet 2016;25:3208–15.
16 Tennese AA, Wevrick R. Impaired hypothalamic regulation of endocrine function
and delayed counterregulatory response to hypoglycemia in Magel2-null mice.
Endocrinology 2011;152:967–78.
17 Buiting K, Di Donato N, Beygo J, Bens S, von der Hagen M, Hackmann K, Horsthemke
B. Clinical phenotypes of MAGEL2 mutations and deletions. Orphanet J Rare Dis
2014;9:40.
18 Tacer KF, Potts PR. Cellular and disease functions of the Prader-Willi Syndrome
geneMAGEL2. Biochem J 2017;474:2177–90.
on 10 August 2018 by guest. Protected by copyright.http://jmg.bmj.com/J Med Genet: first published as 10.1136/jmedgenet-2017-105222 on 29 March 2018. Downloaded from
... By SEP 2020, only more than 120 individuals with pathogenic variants of MAGEL2 were reported worldwide. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Due to the small number of reported cases, the underlying pathological mechanisms and genotypephenotype correlation in MAGEL2-related disorders remain to be elucidated. Moreover, clinical suspicion for SYS is not easy in pediatric patients with hypotonia and DD/ID due to physicians' unfamiliarity. ...
... SYS is an ultra-rare genetic disorder with unknown prevalence. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] In our patient cohort, 0.9% of patients with DD/ID can be expected to suffer from SYS. ...
... No difference in terms of phenotypic severity has been observed between paternally inherited and de novo mutation carriers. [2,3,[6][7][8][9][10][11][12][13][14][15] Based on experimental studies, Wevrick et al suggested that Magel2-null mice show similar symptoms to those in human PWS patients, including neonatal growth retardation, excessive weight gain after weaning, impaired hypothalamic regulation, and reduced fertility. [28,29] However, the precise pathomechanisms of SYS have yet to be elucidated. ...
Article
Full-text available
Schaaf-Yang syndrome (SYS) is a recently identified disorder caused by a loss-of-function mutation in a maternally imprinted gene, MAGEL2, at 15q11.2q13. Due to its extreme rarity and wide range of clinical severity, clinical suspicion is difficult for a physician. In the current study, its frequency among the Korean pediatric patients with developmental delay (DD) or intellectual disability (ID) was assessed. As the first report of Korean patients with SYS, our study aims to increase the awareness of this condition among the physicians taking care of the pediatric patients with DD/ID and hypotonia.The patients diagnosed with SYS by whole-exome sequencing (WES) among the 460 Korean pediatric patients with DD/ID were included, and their clinical and molecular features were reviewed.Four patients (0.9%) were diagnosed with SYS. Profound DD (4 patients), multiple anomalies including joint contractures and facial dysmorphism (4 patients), generalized hypotonia (3 patients), and severe respiratory difficulty requiring mechanical ventilation (3 patients) were noted in most cases, similar to those in previous reports. Sleep apnea (2 patients), autistic features (2 patients), a high grade of gastroesophageal reflux (1 patient), and seizures (1 patient) were found as well. A total of 3 different truncating MAGEL2 mutations were identified. A previously-reported mutation, to be the most common one, c.1996dupC, was found in 2 patients. The other 2 mutations, c.2217delC and c.3449_3450delTT were novel mutations. As MAGEL2 is maternally imprinted, 2 patients had inherited the MAGEL2 mutation from their respective healthy fathers.SYS is an extremely rare cause of DD/ID. However, hypotonia, joint contractures, profound DD/ID and facial dysmorphism are the suggestive clinical features for SYS. As a maternally imprinted disorder, it should be reminded that SYS may be inherited in form of a mutation from a healthy father.
... Infants with SYS typically present with developmental delay, feeding problems, hypotonia, and joint contractures (25,26), followed in childhood by intellectual disability, autism spectrum disorder, and endocrine dysfunction (27,28). Children with SYS have initially been diagnosed with severe hypotonia with respiratory distress (26), recurrent fetal malformations (29), arthrogryposis multiplex congenita and endocrine dysfunction (30), Chitayat-Hall syndrome (distal arthrogryposis, intellectual disability, dysmorphic features and hypopituitarism) (31), Crisponi/cold-induced sweating syndrome (hyperthermia, camptodactyly, feeding and respiratory difficulties, scoliosis) (32), hypotonia/obesity syndrome (33), or Opitz trigonocephaly-C (34). A perinatal lethal phenotype is associated with a specific MAGEL2 mutation (c.1996delC, p.Q666Sfs * 36), and moderate to severe phenotypes are associated with the reciprocal mutation, c.1996dupC (p.Q666Pfs*47, found in 40% of cases) (26)(27)(28)(29)31,(34)(35)(36)(37)(38)(39). ...
... Children with SYS have initially been diagnosed with severe hypotonia with respiratory distress (26), recurrent fetal malformations (29), arthrogryposis multiplex congenita and endocrine dysfunction (30), Chitayat-Hall syndrome (distal arthrogryposis, intellectual disability, dysmorphic features and hypopituitarism) (31), Crisponi/cold-induced sweating syndrome (hyperthermia, camptodactyly, feeding and respiratory difficulties, scoliosis) (32), hypotonia/obesity syndrome (33), or Opitz trigonocephaly-C (34). A perinatal lethal phenotype is associated with a specific MAGEL2 mutation (c.1996delC, p.Q666Sfs * 36), and moderate to severe phenotypes are associated with the reciprocal mutation, c.1996dupC (p.Q666Pfs*47, found in 40% of cases) (26)(27)(28)(29)31,(34)(35)(36)(37)(38)(39). More moderate SYS phenotypes are associated with 39 different protein-truncating mutations located elsewhere in MAGEL2 (27,28). ...
Article
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MAGEL2 encodes the L2 member of the melanoma-associated antigen gene (MAGE) protein family, truncating mutations of which can cause Schaaf-Yang syndrome, an autism spectrum disorder. MAGEL2 is also inactivated in Prader-Willi syndrome, which overlaps clinically and mechanistically with Schaaf-Yang syndrome. Studies to date have only investigated the C-terminal portion of the MAGEL2 protein, containing the MAGE homology domain that interacts with RING-E3 ubiquitin ligases and deubiquitinases to form protein complexes that modify protein ubiquitination. In contrast, the N-terminal portion of the MAGEL2 protein has never been studied. Here, we find that MAGEL2 has a low-complexity intrinsically-disordered N-terminus rich in Pro-Xn-Gly motifs that is predicted to mediate liquid-liquid phase separation to form biomolecular condensates. We used proximity-dependent biotin identification (BioID) and liquid chromatography–tandem mass spectrometry to identify MAGEL2-proximal proteins, then clustered these proteins into functional networks. We determined that coding mutations analogous to disruptive mutations in other MAGE proteins alter these networks in biologically relevant ways. Proteins identified as proximal to the N-terminal portion of MAGEL2 are primarily involved in mRNA metabolic processes, and include three mRNA N 6-methyladenosine (m⁶A)-binding YTHDF proteins and two RNA interference-mediating TNRC6 proteins. We found that YTHDF2 co-immunoprecipitates with MAGEL2, and co-expression of MAGEL2 reduces the nuclear accumulation of YTHDF2 after heat shock. We suggest that the N-terminal region of MAGEL2 may have a role in RNA metabolism, and in particular the regulation of mRNAs modified by m⁶A methylation. These results provide mechanistic insight into pathogenic MAGEL2 mutations associated with Schaaf-Yang syndrome and related disorders.
... [29][30][31] Some truncating variants in MAGEL2 have also been associated with Chitayat-Hall syndrome (CHS). 32 However, a systematic review of all patients with SYS and CHS showed that there is no discernible genetic or clinical difference between both syndromes, and the latter has been renamed as SYS in OMIM. 17 In contrast, two particular MAGEL2 truncating mutations have been recurrently identified in patients affected by lethal arthrogryposis multiplex congenita (AMC), a much more severe phenotype, distinct from SYS. 4 10 27 33 34 All in all, there is no specific constellation of symptoms pathognomonic or specific for any of these clinical syndromes; furthermore, they probably conform to a clinical continuum, therefore denoting the need to address clinical denomination according to molecular findings. ...
Article
Full-text available
Background Schaaf-Yang syndrome (SYS) is caused by truncating mutations in MAGEL2 , mapping to the Prader-Willi region (15q11-q13), with an observed phenotype partially overlapping that of Prader-Willi syndrome. MAGEL2 plays a role in retrograde transport and protein recycling regulation. Our aim is to contribute to the characterisation of SYS pathophysiology at clinical, genetic and molecular levels. Methods We performed an extensive phenotypic and mutational revision of previously reported patients with SYS. We analysed the secretion levels of amyloid-β 1–40 peptide (Aβ 1-40 ) and performed targeted metabolomic and transcriptomic profiles in fibroblasts of patients with SYS (n=7) compared with controls (n=11). We also transfected cell lines with vectors encoding wild-type (WT) or mutated MAGEL2 to assess stability and subcellular localisation of the truncated protein. Results Functional studies show significantly decreased levels of secreted Aβ 1-40 and intracellular glutamine in SYS fibroblasts compared with WT. We also identified 132 differentially expressed genes, including non-coding RNAs (ncRNAs) such as HOTAIR , and many of them related to developmental processes and mitotic mechanisms. The truncated form of MAGEL2 displayed a stability similar to the WT but it was significantly switched to the nucleus, compared with a mainly cytoplasmic distribution of the WT MAGEL2. Based on the updated knowledge, we offer guidelines for the clinical management of patients with SYS. Conclusion A truncated MAGEL2 protein is stable and localises mainly in the nucleus, where it might exert a pathogenic neomorphic effect. Aβ 1-40 secretion levels and HOTAIR mRNA levels might be promising biomarkers for SYS. Our findings may improve SYS understanding and clinical management.
... [29][30][31] Some truncating variants in MAGEL2 have also been associated with Chitayat-Hall syndrome (CHS). [32] However, a systematic review of all SYS and CHS patients showed that there is no discernible genetic or clinical difference between both syndromes, and the latter has been renamed as SYS in OMIM. [17] In contrast, two particular MAGEL2 truncating mutations have been recurrently identified in patients affected by lethal arthrogryposis multiplex congenita (AMC), a much more severe phenotype, distinct from SYS. [4,10,27,33,34] All in all, there is no specific constellation of symptoms pathognomonic or specific for any of these clinical syndromes; furthermore, they probably conform to a clinical continuum, therefore denoting the need to address clinical denomination according to molecular findings. ...
Preprint
Full-text available
Background Schaaf-Yang syndrome (SYS) is caused by truncating mutations in MAGEL2 , mapping to the Prader-Willi region (15q11-q13), with an observed phenotype partially overlapping that of Prader-Willi syndrome. MAGEL2 plays a role in retrograde transport and protein recycling regulation. Our aim is to contribute to the characterization of SYS pathophysiology at clinical, genetic and molecular levels. Methods We performed an extensive phenotypic and mutational revision of previously reported SYS patients. We analysed the secretion levels of amyloid-β 1-40 peptide (Aβ 1-40 ), and performed targeted metabolomic and transcriptomic profiles in SYS patients’ fibroblasts (n=7) compared to controls (n=11). We also transfected cell lines with vectors encoding wild-type (WT) or truncated MAGEL2 to assess stability and subcellular localization of the truncated protein. Results Functional studies show significantly decreased levels of secreted Aβ 1-40 and intracellular glutamine in SYS fibroblasts compared to wild-type. We also identified 132 differentially expressed genes, including ncRNAs such as HOTAIR, many of them related to developmental processes and mitotic mechanisms. The truncated form of MAGEL2 displayed a stability similar to the wild-type but it was significantly switched to the nucleus, compared to a mainly cytoplasmic distribution of the wild-type MAGEL2. Based on updated knowledge we offer guidelines for clinical management of SYS patients. Conclusion A truncated MAGEL2 protein is stable and localises mainly in the nucleus, where it might exert a pathogenic gain of function effect. Aβ 1-40 secretion levels and HOTAIR mRNA levels might be promising biomarkers for SYS. Our findings may improve SYS understanding and clinical management. Key Messages MAGEL2 truncating mutations cause Schaaf-Yang syndrome (SYS) but the functional effects of the truncated MAGEL2 protein have been poorly defined. By expressing truncated MAGEL2 in cell lines, we now know that a truncated version of the protein is retained in the nucleus, thus exerting a gain-of-function behaviour in addition to the loss of some of its main functions. Patients’ fibroblasts show reduced levels of excreted amyloid beta 1-40 and intracellular glutamine as well as an altered transcriptomic profile, including overexpression of the major regulator HOTAIR. Based on a comprehensive review of genetic and clinical aspects of all reported cases, families and physicians will benefit from the Clinical Management Recommendations that we provide here.
... The ERCC5 gene was most frequently implicated gene in cases from France, Brazil, Spain and Portugal with a fetal presentation, seen in 10/13 cases (Baer et al., 2020). tures can also be seen in multiple pterygium syndrome and is also reported with KIAA1109 and MAGEL2 mutations (Gueneau et al., 2018;Jobling et al., 2018). Most patients with MAGEL2 mutations or Schaaf-Yang syndrome have a Prader-Willi like phenotype with neonatal hypotonia, almond shaped eyes, obesity, and sleep apneas, but some patients can present with fetal akinesia, contractures and in-utero death. ...
Article
Fetal akinesia and contractures can be caused by mutations in various genes that lead to overlapping phenotypes with contractures, rocker bottom feet, cerebellar hypoplasia, ventriculomegaly, growth retardation, pulmonary hypoplasia, cystic hygroma and cleft palate in various combinations. Cerebro‐oculo‐facio‐skeletal (COFS) syndrome is a condition resulting from defects in DNA repair pathway, and genes involved include ERCC1 (COFS), ERCC2 (XPD), ERCC5(XPG), and ERCC6 (CSB). It is a severe disorder presenting in fetal or neonatal period with microcephaly, arthrogryposis, prominent nose, and kyphoscoliosis, and leads to early death in childhood. We report a baby with antenatally identified arthrogryposis in which the homozygous pathogenic variant in exon 8 was identified in ERCC5 gene, by targeted next generation sequencing. This was predicted to cause premature chain termination in the protein. ERCC5 gene is mainly implicated in xeroderma pigmentosum, sometimes in COFS syndrome.
... Schaaf-Yang syndrome was initially described in patient cohorts consisting predominantly of children, while adults with SHFYNG have been underrepresented. Adult individuals with MAGEL2 mutations have been reported in the literature, such as the cases presented by Jobling et al. (individual I-1) [15], or Fountain et al. (individual 18) [13], but a systematic investigation of adults with this disorder has not been done previously. The phenotypes observed in these individuals are highly variable, especially with regard to the degree of personal independence and social participation, ranging from semi-autonomous living (individual #4) to complete dependence on external help (individual #3). ...
Article
Full-text available
Background MAGEL2 -associated Schaaf-Yang syndrome (SHFYNG, OMIM #615547, ORPHA: 398069), which was identified in 2013, is a rare disorder caused by truncating variants of the paternal copy of MAGEL2 , which is localized in the imprinted region on 15q11.2q13. The phenotype of SHFYNG in childhood partially overlaps with that of the well-established Prader–Willi syndrome (PWS, OMIM #176270). While larger numbers of younger individuals with SHFYNG have been recently published, the phenotype in adulthood is not well established. We recruited 7 adult individuals (aged 18 to 36) with molecularly confirmed SHFYNG and collected data regarding the clinical profile including eating habits, sleep, behavior, personal autonomy, psychiatric abnormalities and other medical conditions, as well as information about the respective phenotypes in childhood. Results Within our small cohort, we identified a range of common features, such as disturbed sleep, hypoactivity, social withdrawal and anxiety, but also noted considerable differences at the level of personal autonomy and skills. Behavioral problems were frequent, and a majority of individuals displayed weight gain and food-seeking behavior, along with mild intellectual disability or borderline intellectual function. Classical symptoms of SHFYNG in childhood were reported for most individuals. Conclusion Our findings indicate a high variability of the functional abilities and social participation of adults with SHFYNG. A high prevalence of obesity within our cohort was notable, and uncontrollable food intake was a major concern for some caregivers. The phenotypes of PWS and SHFYNG in adulthood might be more difficult to discern than the phenotypes in childhood. Molecular genetic testing for SHFYNG should therefore be considered in adults with the suspected diagnosis of PWS, if testing for PWS has been negative.
Article
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Congenital hypopituitarism is a genetically heterogeneous condition that is part of a spectrum disorder that can include holoprosencephaly. Heterozygous mutations in SIX3 cause variable holoprosencephaly in humans and mice. We identified two children with neonatal hypopituitarism and thin pituitary stalk who were doubly heterozygous for rare, likely deleterious variants in the transcription factors SIX3 and POU1F1. We used genetically engineered mice to understand the disease pathophysiology. Pou1f1 loss of function heterozygotes are unaffected; Six3 heterozygotes have pituitary gland dysmorphology and incompletely ossified palate; and the Six3+/−; Pou1f1+/dw double; heterozygote mice have a pronounced phenotype, including pituitary growth through the palate. The interaction of Pou1f1 and Six3 in mice supports the possibility of digenic pituitary disease in children. Disruption of Six3 expression in the oral ectoderm completely ablated anterior pituitary development, and deletion of Six3 in the neural ectoderm blocked development of the pituitary stalk and both anterior and posterior pituitary lobes. Six3 is required in both oral and neural ectodermal tissues for activation of signaling pathways and transcription factors necessary for pituitary cell fate. These studies clarify the mechanism of SIX3 action in pituitary development and provide support for a digenic basis for hypopituitarism.
Poster
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We are presenting the case of a 17-year-old female of Hispanic descent who was referred to the Genetics clinic when she was 13-year-old due to a diagnosis of autism spectrum disorder (ASD). Initial metabolic laboratory workup was negative as well as karyotype analysis, Fragile X and chromosomal microarray studies. Autism Disorder-Intellectual disabilities gene panel showed mutations on the MAGEL2 and SMARCA4 genes. MAGEL2 is located in a chromosomal region strongly associated with Prader-Willi syndrome (PWS). Mutations in this gene have been associated with Chitayat-Hall (CHS) and Schaaf-Yang (SYS) syndromes. SMARCA4 mutations have been associated with Coffin Siris Syndrome. Both CHS and SYS have been described as part of a phenotypic continuum underlining the possible pleiotropy that mutations in this gene produces. It has also been described that MAGEL2 complete mutations rather than truncating mutations lead to a milder phenotype. This suggest a possible dominant-negative effect or a leaky expression of the maternal MAGEL2 allele.
Article
Prader-Willi syndrome (PWS) is a rare genetic syndrome, caused by the loss of expression of the paternal chromosome 15q11-q13 region. Over the past years, many cases of patients with characteristics similar to PWS, but without a typical genetic aberration of the 15q11-q13 region, have been described. These patients are often labelled as Prader-Willi-like (PWL). PWL is an as-yet poorly defined syndrome, potentially affecting a significant number of children and adults. In the current clinical practice, patients labelled as PWL are mostly left without treatment options. Considering the similarities with PWS, children with PWL might benefit from the same care and treatment as children with PWS. This review gives more insight into the pheno- and genotype of PWL and includes 86 papers, containing 368 cases of patients with a PWL phenotype. We describe mutations and aberrations for consideration when suspicion of PWS remains after negative testing. The most common genetic diagnoses were Temple syndrome (formerly known as maternal uniparental disomy 14), Schaaf-Yang syndrome (truncating mutation in the MAGEL2 gene), 1p36 deletion, 2p deletion, 6q deletion, 6q duplication, 15q deletion,15q duplication, 19p deletion, fragile X syndrome and Xq duplication. We found that the most prevalent symptoms in the entire group were developmental delay/intellectual disability (76%), speech problems (64%), overweight/obesity (57%), hypotonia (56%) and psycho-behavioral problems (53%).In addition, we propose a diagnostic approach to patients with a PWL phenotype for (pediatric) endocrinologists. PWL comprises a complex and diverse group of patients, which calls for multidisciplinary care with an individualized approach.
Article
Schaaf-Yang syndrome is a genetic disorder caused by mutations in the paternal allele of the MAGEL2 gene. Developmental delay, feeding difficulties, joint contractures and a high prevalence of autism spectrum disorders are characteristic of the syndrome. Endocrine abnormalities include mostly various pituitary hormonal deficiencies, presenting as hypoglycemia in 48% of reported cases. Persistent hyperinsulinism was only described in two siblings and responded to diazoxide treatment. We describe a unique case of an infant with Schaaf-Yang syndrome that presented with persistent hyperinsulinism unresponsive to diazoxide. Furthermore, we conducted a literature review of the endocrine abnormalities described in MAGEL2 related disorders. The case presented expands the clinical phenotype of Schaaf-Yang syndrome and emphasizes the importance of endocrine follow-up in these patients. Further investigation into the role of MAGEL2 in the regulation of pancreatic beta-cell insulin secretion, will improve our understanding of the abnormalities in glucose regulation in this syndrome.
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The Human Gene Mutation Database (HGMD®) constitutes a comprehensive collection of published germline mutations in nuclear genes that underlie, or are closely associated with human inherited disease. At the time of writing (March 2017), the database contained in excess of 203,000 different gene lesions identified in over 8000 genes manually curated from over 2600 journals. With new mutation entries currently accumulating at a rate exceeding 17,000 per annum, HGMD represents de facto the central unified gene/disease-oriented repository of heritable mutations causing human genetic disease used worldwide by researchers, clinicians, diagnostic laboratories and genetic counsellors, and is an essential tool for the annotation of next-generation sequencing data. The public version of HGMD (http://www.hgmd.org) is freely available to registered users from academic institutions and non-profit organisations whilst the subscription version (HGMD Professional) is available to academic, clinical and commercial users under license via QIAGEN Inc.
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Opitz trigonocephaly C syndrome (OTCS) is a rare genetic disorder characterized by craniofacial anomalies, variable intellectual and psychomotor disability, and variable cardiac defects with a high mortality rate. Different patterns of inheritance and genetic heterogeneity are known in this syndrome. Whole exome and genome sequencing of a 19-year-old girl (P7), initially diagnosed with OTCS, revealed a de novo nonsense mutation, p.Q638*, in the MAGEL2 gene. MAGEL2 is an imprinted, maternally silenced, gene located at 15q11-13, within the Prader-Willi region. Patient P7 carried the mutation in the paternal chromosome. Recently, mutations in MAGEL2 have been described in Schaaf-Yang syndrome (SHFYNG) and in severe arthrogryposis. Patient P7 bears resemblances with SHFYNG cases but has other findings not described in this syndrome and common in OTCS. We sequenced MAGEL2 in nine additional OTCS patients and no mutations were found. This study provides the first clear molecular genetic basis for an OTCS case, indicates that there is overlap between OTCS and SHFYNG syndromes, and confirms that OTCS is genetically heterogeneous. Genes encoding MAGEL2 partners, either in the retrograde transport or in the ubiquitination-deubiquitination complexes, are promising candidates as OTCS disease-causing genes.
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Prader-Willi syndrome (PWS) is a genetic disorder characterized by a variety of physiological and behavioral dysregulations, including hyperphagia, a condition that can lead to life-threatening obesity. Feeding behavior is a highly complex process with multiple feedback loops that involve both peripheral and central systems. The arcuate nucleus of the hypothalamus (ARH) is critical for the regulation of homeostatic processes including feeding, and this nucleus develops during neonatal life under of the influence of both environmental and genetic factors. Although much attention has focused on the metabolic and behavioral outcomes of PWS, an understanding of its effects on the development of hypothalamic circuits remains elusive. Here, we show that mice lacking Magel2, one of the genes responsible for the etiology of PWS, display an abnormal development of ARH axonal projections. Notably, the density of anorexigenic α-melanocyte-stimulating hormone axons was reduced in adult Magel2-null mice, while the density of orexigenic agouti-related peptide fibers in the mutant mice appeared identical to that in control mice. Based on previous findings showing a pivotal role for metabolic hormones in hypothalamic development, we also measured leptin and ghrelin levels in Magel2-null and control neonates and found that mutant mice have normal leptin and ghrelin levels. In vitro experiments show that Magel2 directly promotes axon growth. Together, these findings suggest that a loss of Magel2 leads to the disruption of hypothalamic feeding circuits, an effect that appears to be independent of the neurodevelopmental effects of leptin and ghrelin and likely involves a direct neurotrophic effect of Magel2.
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ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) at the National Center for Biotechnology Information (NCBI) is a freely available archive for interpretations of clinical significance of variants for reported conditions. The database includes germline and somatic variants of any size, type or genomic location. Interpretations are submitted by clinical testing laboratories, research laboratories, locus-specific databases, OMIM®, GeneReviews™, UniProt, expert panels and practice guidelines. In NCBI's Variation submission portal, submitters upload batch submissions or use the Submission Wizard for single submissions. Each submitted interpretation is assigned an accession number prefixed with SCV. ClinVar staff review validation reports with data types such as HGVS (Human Genome Variation Society) expressions; however, clinical significance is reported directly from submitters. Interpretations are aggregated by variant-condition combination and assigned an accession number prefixed with RCV. Clinical significance is calculated for the aggregate record, indicating consensus or conflict in the submitted interpretations. ClinVar uses data standards, such as HGVS nomenclature for variants and MedGen identifiers for conditions. The data are available on the web as variant-specific views; the entire data set can be downloaded via ftp. Programmatic access for ClinVar records is available through NCBI's E-utilities. Future development includes providing a variant-centric XML archive and a web page for details of SCV submissions.
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Arthrogryposis multiplex congenita (AMC) is characterized by the presence of multiple joint contractures resulting from reduced or absent fetal movement. Here, we report two unrelated families affected by lethal AMC. By genetic mapping and whole-exome sequencing in a multiplex family, a heterozygous truncating MAGEL2 mutation leading to frameshift and a premature stop codon (c.1996delC, p.Gln666Serfs(∗)36) and inherited from the father was identified in the probands. In another family, a distinct heterozygous truncating mutation leading to frameshift (c.2118delT, p.Leu708Trpfs(∗)7) and occurring de novo on the paternal allele of MAGEL2 was identified in the affected individual. In both families, RNA analysis identified the mutated paternal MAGEL2 transcripts only in affected individuals. MAGEL2 is one of the paternally expressed genes within the Prader-Willi syndrome (PWS) locus. PWS is associated with, to varying extents, reduced fetal mobility, severe infantile hypotonia, childhood-onset obesity, hypogonadism, and intellectual disability. MAGEL2 mutations have been recently reported in affected individuals with features resembling PWS and called Schaaf-Yang syndrome. Here, we show that paternal MAGEL2 mutations are also responsible for lethal AMC, recapitulating the clinical spectrum of PWS and suggesting that MAGEL2 is a PWS-determining gene.
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Neurodevelopmental disorders (NDDs) affect more than 3% of children and are attributable to single-gene mutations at more than 1000 loci. Traditional methods yield molecular diagnoses in less than one-half of children with NDD. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) can enable diagnosis of NDD, but their clinical and cost-effectiveness are unknown. One hundred families with 119 children affected by NDD received diagnostic WGS and/or WES of parent-child trios, wherein the sequencing approach was guided by acuity of illness. Forty-five percent received molecular diagnoses. An accelerated sequencing modality, rapid WGS, yielded diagnoses in 73% of families with acutely ill children (11 of 15). Forty percent of families with children with nonacute NDD, followed in ambulatory care clinics (34 of 85), received diagnoses: 33 by WES and 1 by staged WES then WGS. The cost of prior negative tests in the nonacute patients was $19,100 per family, suggesting sequencing to be cost-effective at up to $7640 per family. A change in clinical care or impression of the pathophysiology was reported in 49% of newly diagnosed families. If WES or WGS had been performed at symptom onset, genomic diagnoses may have been made 77 months earlier than occurred in this study. It is suggested that initial diagnostic evaluation of children with NDD should include trio WGS or WES, with extension of accelerated sequencing modalities to high-acuity patients. Copyright © 2014, American Association for the Advancement of Science.
Article
Melanoma antigen L2 (MAGEL2 or MAGE-L2) is a member of the MAGE family of ubiquitin ligase regulators. It is maternally imprinted and often paternally deleted or mutated in the related neurodevelopmental syndromes, Prader-Willi Syndrome (PWS) and Schaaf- Yang Syndrome (SHFYNG). MAGEL2 is highly expressed in the hypothalamus and plays an important role in a fundamental cellular process that recycles membrane proteins from endosomes through the retromer sorting pathway. MAGEL2 is part of a multi-subunit protein complex consisting of MAGEL2, the TRIM27 E3 ubiquitin ligase, and the USP7 deubiquitinating enzyme. The MAGEL2-USP7-TRIM27 (or MUST) complex facilitates the retromer recycling pathway through ubiquitination and activation of the WASH actin nucleation promoting factor. This review provides an overview of the MAGE protein family of ubiquitin ligases regulators and details the molecular and cellular role of MAGEL2 in ubiquitination, actin regulation and endosomal sorting processes, as well as MAGEL2 implications in PWS and SHFYNG disorders. The physiological functions of MAGEL2, elucidated through the study of Magel2 knockout mouse models, are also discussed. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.
Article
Purpose: Truncating mutations in the maternally imprinted, paternally expressed gene MAGEL2, which is located in the Prader-Willi critical region 15q11-13, have recently been reported to cause Schaaf-Yang syndrome, a Prader-Willi-like disease that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties, and autism spectrum disorder. The causality of the reported variants in the context of the patients' phenotypes was questioned, as MAGEL2 whole-gene deletions seem to cause little or no clinical phenotype. Methods: Here we report a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families, including 1 family with 3 individuals found to be affected with a truncating variant of MAGEL2, 11 individuals who are clinically affected but were not tested molecularly, and a presymptomatic fetal sibling carrying the pathogenic MAGEL2 variant. Results: All cases harbor truncating mutations of MAGEL2, and nucleotides c.1990-1996 arise as a mutational hotspot, with 10 individuals and 1 fetus harboring a c.1996dupC (p.Q666fs) mutation and 2 fetuses harboring a c.1996delC (p.Q666fs) mutation. The phenotypic spectrum of Schaaf-Yang syndrome ranges from fetal akinesia to neurobehavioral disease and contractures of the small finger joints. Conclusion: This study provides strong evidence for the pathogenicity of truncating mutations of the paternal allele of MAGEL2, refines the associated clinical phenotypes, and highlights implications for genetic counseling for affected families.Genet Med advance online publication 19 May 2016Genetics in Medicine (2016); doi:10.1038/gim.2016.53.
Article
Prader–Willi syndrome (PWS) is caused by the loss of expression of imprinted genes in chromosome 15q11–q13. Affected individuals exhibit neonatal hypotonia, developmental delay and childhoodonset obesity. Necdin, a protein implicated in the terminal differentiation of neurons, is the only PWS candidate gene to reduce viability when disrupted in a mouse model. In this study, we have characterized MAGEL2 (also known as NDNL1), a gene with 51% amino acid sequence similarity to necdin and located 41 kb distal to NDN in the PWS deletion region. MAGEL2 is expressed predominantly in brain, the primary tissue affected in PWS and in several fetal tissues as shown by northern blot analysis. MAGEL2 is imprinted with monoallelic expression in control brain, and paternal-only expression in the central nervous system as demonstrated by its lack of expression in brain from a PWS-affected individual. The orthologous mouse gene (Magel2) is located within 150 kb of Ndn, is imprinted with paternal-only expression and is expressed predominantly in late developmental stages and adult brain as shown by northern blotting, RT–PCR and whole-mount RNA in situ hybridization. Magel2 distribution partially overlaps that of Ndn, with strong expression being detected in the central nervous system in midgestation mouse embryos by in situ hybridization. We hypothesize that, although loss of necdin expression may be important in the neonatal presentation of PWS, loss of MAGEL2 may be critical to abnormalities in brain development and dysmorphic features in individuals with PWS.