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A familial chromosome 4p16.3 terminal microdeletion that does not cause Wolf-Hirschhorn (4p-) syndrome

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Mayowa Azeez Osundiji
Mayowa Azeez Osundiji
Mayowa Azeez Osundiji
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Eva Kahn
Eva Kahn
Eva Kahn
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Brendan Lanpher
Brendan Lanpher
Brendan Lanpher
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Abstract and Figures

Chromosome 4p16.3 microdeletions are known to cause Wolf–Hirschhorn syndrome (WHS), which is characterized by a distinct craniofacial gestalt and multiple congenital malformations. The 4p16.3 region encompasses WHS critical region 1 (WHSCR1) and 2 (WHSCR2). The WHSCR contains several genes that have been implicated in the WHS phenotype including: WHS candidate 1 [WHSC1 (aka NSD2, OMIM 602952)], WHS candidate 2 [WHSC2 (aka NELFA, OMIM 606026)], and LETM1 (OMIM 604407). Although several patients harboring 4p16.3 microdeletions that are associated with WHS phenotypes have been reported, the precise molecular underpinnings of WHS are subjects of active investigations. The potential role(s) of genes within the 4p16.3 are increasingly being investigated. Here we report a novel 4p16.3 terminal microdeletion that is not associated with the characteristic WHS phenotype. We studied Individual A (7-months-old female) and her father, Individual B (27-year-old), who both carry a terminal 4p16.3 microdeletion (about 555 kb) that is distal to the WHSCR1 and WHSCR2, and does not include WHSC1, WHSC2, or LETM1. Overall, our findings expand the phenotypic spectrum associated with 4p16.3 microdeletions and support the previous observations that, in some individuals, microdeletions within 4p16.3 region may not be sufficient to cause WHS.
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Vol.: (0123456789)
Chromosome Res (2024) 32:13
https://doi.org/10.1007/s10577-024-09757-9
CASE REPORT
A familial chromosome 4p16.3 terminal microdeletion
thatdoes notcause Wolf‑Hirschhorn (4p‑) syndrome
MayowaAzeezOsundiji· EvaKahn·
BrendanLanpher
Received: 12 June 2024 / Revised: 28 September 2024 / Accepted: 22 October 2024
© The Author(s), under exclusive licence to Springer Nature B.V. 2024
observations that, in some individuals, microdele-
tions within 4p16.3 region may not be sufficient to
causeWHS.
Keywords WHS· Microdeletion· Chromosome
Abbreviations
WHS Wolf-Hirschhorn syndrome
WHSCR WHS critical region
WHSC WHS candidate
ADHD Attention-deficit/hyperactivity disorder
FISH Fluorescence insitu hybridization
SNP Single nucleotide polymorphism
IUGR Intrauterine growth restriction
Introduction
Wolf-Hirschhorn syndrome (WHS, OMIM 194190)
is a chromosomal disorder that is characterized by a
distinct craniofacial gestalt [the Greek-warrior helmet
appearance (wide forehead with prominent glabella),
large and protruding eyes, hypertelorism, down-
turned corners of the mouth, and micrognathia], pre
and post-natal growth restriction (including micro-
cephaly), intellectual disability, hypotonia, seizures
and congenital malformations (Battaglia etal. 2015).
Heterozygous partial deletion of the distal segment
of the p arm of chromosome 4 (4p) results in WHS.
The initial cases of WHS were mapped to the 4pter
region using conventional cytogenetic techniques
Abstract Chromosome 4p16.3 microdeletions are
known to cause Wolf–Hirschhorn syndrome (WHS),
which is characterized by a distinct craniofacial
gestalt and multiple congenital malformations. The
4p16.3 region encompasses WHS critical region 1
(WHSCR1) and 2 (WHSCR2). The WHSCR contains
several genes that have been implicated in the WHS
phenotype including: WHS candidate 1 [WHSC1
(aka NSD2, OMIM 602952)], WHS candidate 2
[WHSC2(akaNELFA, OMIM 606026)],and LETM1
(OMIM 604407). Although several patients harboring
4p16.3 microdeletions that are associated with WHS
phenotypes have been reported, the precise molecular
underpinnings of WHS are subjects of active inves-
tigations. The potential role(s) of genes within the
4p16.3 are increasingly being investigated. Here we
report a novel 4p16.3 terminal microdeletion that is
not associated with the characteristic WHS pheno-
type. We studied Individual A (7-months-old female)
and her father, Individual B (27-year-old), who both
carry a terminal 4p16.3 microdeletion (about 555kb)
that is distal to the WHSCR1 and WHSCR2, and does
not include WHSC1, WHSC2, or LETM1. Overall,our
findings expand the phenotypic spectrum associated
with 4p16.3microdeletionsand support the previous
Responsible Editor: Amy Breman
M.A.Osundiji· E.Kahn· B.Lanpher(*)
Department ofClinical Genomics, Mayo Clinic, 200 First
Street SW, Rochester, MN55905, USA
e-mail: Lanpher.Brendan@mayo.edu
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
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Identification of an 85-kb Heterozygous 4p Microdeletion With Full Genome Analysis in Autosomal Dominant Charcot-Marie-Tooth Disease
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  • Jun 2023
Background and Objectives Charcot-Marie-Tooth disease (CMT) is a syndrome of a hereditary neurodegenerative condition affecting the peripheral nervous system and is a single gene disorder. Deep phenotyping coupled with advanced genetic techniques is critical in discovering new genetic defects of rare genetic disorders such as CMT. Methods We applied multidisciplinary investigations to examine the neurophysiology and nerve pathology in a family that fulfilled the diagnosis of CMT2. When phenotype-guided first-tier genetic tests and whole-exome sequencing did not yield a molecular diagnosis, we conducted full genome analysis by examining phased whole-genome sequencing and whole-genome optical mapping data to search for the causal variation. We then performed a systematic review to compare the reported patients with interstitial microdeletion in the short arm of chromosome 4. Results In this family with CMT2, we reported the discovery of a heterozygous 85-kb microdeletion in the short arm of chromosome 4 (4p16.3)[NC_000004.12:g.1733926_1819031del] spanning 3 genes [ TACC3 (intron 6-exon 16), FGFR3 (total deletion), and LETM1 (intron 10-exon14)] that cosegregated with disease phenotypes in family members. The clinical features of peripheral nerve degeneration in our family are distinct from the well-known 4p microdeletion syndrome of Wolf-Hirschhorn syndrome, in which brain involvement is the major phenotype. Discussion In summary, we used the full genome analysis approach to discover a new microdeletion in a family with CMT2. The deleted segment contains 3 genes ( TACC3 , FGFR3 , and LETM1 ) that likely play a role in the pathogenesis of nerve degeneration.
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Distinct Epileptogenic Mechanisms Associated with Seizures in Wolf-Hirschhorn Syndrome
Article
Full-text available
  • May 2022
  • MOL NEUROBIOL
Seizures are one of the clinical hallmarks of Wolf-Hirschhorn syndrome (WHS), causing a significant impact on the life quality , still in the first years of life. Even that the knowledge about WHS-related seizure candidate genes has grown, cumulative evidence suggests synergic haploinsufficiency of distinct genes within cellular networks that should be better elucidated. Herein, we evaluated common mechanisms between candidate genes from WHS seizure-susceptibility regions (SSR) and genes globally associated with epilepsy. For this purpose, data from 94 WHS patients delineated by chromosomal microarray analysis were integrated into a tissue-specific gene network with gene expression, drugs, and biological processes. We found functional modules and signaling pathways involving candidate and new genes with potential involvement in the WHS-related seizure phenotype. The proximity among the previous reported haploinsufficient candidate genes (PIGG, CPLX1, CTBP1, LETM1) and disease genes associated with epilepsy suggests not just one, but different impaired mechanisms in cellular networks responsible for the balance of neuronal activity in WHS patients, from which neuron communication is the most impaired in WHS-related seizures. Furthermore, CTBP1 obtained the largest number of drug associations, reinforcing its importance for adaptations of brain circuits and its putative use as a pharmacological target for treating seizures/epilepsy in patients with WHS.
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Wolf-Hirschhorn Syndrome: Clinical and Genetic Study of 7 New Cases, and Mini Review
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  • Aug 2021
Wolf–Hirschhorn syndrome (WHS), a rare disorder determined by distal 4p deletion, is characterized by a pre and postnatal growth retardation, hypotonia, intellectual disability, epilepsy, craniofacial dysmorphism, and congenital fusion anomalies. The clinical aspects are dependent on the deletion’ size. Our aim was to identify rare specific characteristics in a cohort of seven cases with 4p deletion and to assess the utility of Multiplex ligation-dependent probe amplification (MLPA) (cheap and sensitive test)—combined kits—as a diagnostic test and selection tool for cases that require other investigations (chromosomal microarray analysis—CMA, karyotype). For all cases we conducted a clinical examination with the main features identified: facial dysmorphism, intellectual disability, postnatal development delay, cardiac defects and hypotonia. In some cases, we observed seizures, structural brain abnormalities, immunodeficiencies, and renal anomalies. Prenatal growth retardation was detected in a relatively small number of cases, but postnatal growth failure was a constant feature. In all cases, the clinical diagnosis was confirmed by genetic analyses: karyotype and/or MLPA. In conclusion, renal and brain defects, as well as immunodeficiency are rare manifestations and should be looked for. Although CMA is the standard test, in our experience, MLPA is also a reliable screening method as the identified cases were either confirmed by MLPA or selected for further investigations.
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Disorders of sex development in Wolf–Hirschhorn syndrome: a genotype–phenotype correlation and MSX1 as candidate gene
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  • Feb 2021
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Wolf–Hirschhorn syndrome: A review and update
Article
Full-text available
  • Aug 2015
  • AM J MED GENET C
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Unusual 4p16.3 deletions suggest an additional chromosome region for the Wolf-Hirschhorn syndrome-Associated seizures disorder
Article
Full-text available
Objective: Seizure disorder is one of the most relevant clinical manifestations in Wolf-Hirschhorn syndrome (WHS) and it acts as independent prognostic factor for the severity of intellectual disability (ID). LETM1, encoding a mitochondrial protein playing a role in K(+) /H(+) exchange and in Ca(2+) homeostasis, is currently considered the major candidate gene. However, whether haploinsufficiency limited to LETM1 is enough to cause epilepsy is still unclear. The main purpose of the present research is to define the 4p chromosome regions where genes for seizures reside. Methods: Comparison of our three unusual 4p16.3 deletions with 13 literature reports. Array-comparative genomic hybridization (a-CGH). Real-time polymerase chain reaction (RT-PCR) on messanger RNA (mRNA) of LETM1 and CPLX1. Direct sequencing of LETM1. Results: Three unusual 4p16.3 deletions were detected by array-CGH in absence of a obvious clinical diagnosis of WHS. Two of these, encompassing LETM1, were found in subjects who never had seizures. The deletions were interstitial, spanning 1.1 Mb with preservation of the terminal 1.77 Mb region in one case and 0.84 Mb with preservation of the terminal 1.07 Mb region in the other. The other deletion was terminal, affecting a 0.564 Mb segment, with preservation of LETM1, and it was associated with seizures and learning difficulties. Upon evaluating our patients along with literature reports, we noted that six of eight subjects with terminal 4p deletions preserving LETM1 had seizures, whereas seven of seven with interstitial deletions including LETM1 and preserving the terminal 1 Mb region on 4p did not. An additional chromosome region for seizures is suggested, falling within the terminal 1.5 Mb on 4p, not including LETM1. Significance: We consider that haploinsufficiency not limited to LETM1 but including other genes acts as a risk factor for the WHS-associated seizure disorder, according to a comorbidity model of pathogenesis. Additional candidate genes reside in the terminal 1.5 Mb region on 4p, most likely distal to LETM1. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
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Letm1, the mitochondrial Ca2+/H+ antiporter, is essential for normal glucose metabolism and alters brain function in Wolf-Hirschhorn syndrome
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Full-text available
  • May 2013
  • P NATL ACAD SCI USA
Significance Wolf–Hirschhorn syndrome (WHS), caused by deletions in 4p16.3, was the first recognized subtelomeric deletion syndrome. As with other syndromes of this class, WHS has not yet been subjected to an intensive, systematic analysis using mouse or cellular models. We recently identified leucine zipper-EF-hand containing transmembrane protein 1 (Letm1) as a mitochondrial Ca ²⁺ /H ⁺ antiporter, located in the core WHS region. In this study, Letm1 null mice were generated and characterized. Deletion of Letm1 disrupts early embryonic development, reduces glucose oxidation and thus particularly affects brain function.
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Chromosomal aberrations in human disease
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A brief history of the development of modern technics in human cytogenetics is presented, and application of these technics to the study of human disease is illustrated.
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Association of Mitochondrial Letm1 with Epileptic Seizures
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  • May 2013
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Leucine zipper-EF-hand containing transmembrane protein 1 (Letm1) is a mitochondrial protein that is associated with seizure attacks in Wolf-Hirschhorn syndrome. This study aimed to investigate the expression pattern of Letm1 in patients with temporal lobe epilepsy (TLE) and pilocarpine-induced rat model of epilepsy, and to determine if altered Letm1 leads to mitochondrial dysfunction and increased susceptibility to seizures. Using immunohistochemical, immunofluorescent, western blotting, and transmission electron microscopic methods, we have found that Letm1 was significantly decreased in TLE patients, and gradually decreased in experimental rats from 1 to 7 days after onset of seizures. Letm1 knock-down by a lentivirus bearing LV-Letm1-sh resulted in mitochondrial swelling and decreased expression of Letm1 target protein mitochondrially encoded cytochrome B (MT-CYB). Behavioral study revealed that inhibition of Letm1 caused early onset of the first seizure, increased seizure frequency, and duration. However, administration of Letm1 homolog nigericin failed to prevent epilepsy. These results indicate that inhibition of Letm1 and mitochondrial dysfunctions contributes to the development of epileptic seizures. Appropriate Letm1 level may be critical for maintaining normal neuronal functions. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected] /* */
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109 kb Deletion of Chromosome 4p16.3 in a Patient With Mild Phenotype of Wolf-Hirschhorn Syndrome
Article
  • Jun 2013
  • AM J MED GENET A
Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion syndrome associated with growth retardation, developmental disabilities, epileptic seizures, and distinct facial features resulting from a deletion of the short arm of chromosome 4. The Wolf-Hirschhorn Syndrome Critical Region WHSCR2 includes the LETM1 gene and 5' end of the WHSC1 gene. A haploinsufficiency of WHSC1 is thought to be responsible for a number of WHS characteristics. We report on a 2-year-old male with severe growth retardation, microcephaly and a characteristic facial appearance. He had no internal anomalies and his developmental milestones were mildly delayed. An array-CGH analysis revealed loss of genomic copy numbers in the region 4p16.3, which included FGFR3, LETM1, and WHSC1. The size of the deletion was only 109 kb. The deletion included the important genes in WHSCR2. We suspect that haploinsufficiency of WHSC1 is the most probable cause of the growth deficiency, microcephaly, and characteristic facial features in WHS. © 2013 Wiley Periodicals, Inc.
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