Sarina G Kant

Leiden University, Leyden, South Holland, Netherlands

Are you Sarina G Kant?

Claim your profile

Publications (66)366.52 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The fast technological development, particularly SNP array, array-comparative genomic hybridization and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways and fundamental cellular processes, followed by chromosomal aberrations including copy number variants and imprinting disorders associated with short stature. Many novel causes of growth hormone (GH) deficiency as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GH deficiency are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3 and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFκB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T3/T4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in approximately 3% of short children, and also rasopathies (e.g. Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, copy number variants and imprinting disorders.
    No preview · Article · Nov 2015 · European Journal of Endocrinology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Context: Several patients with Beckwith Wiedemann Syndrome (BWS) with multiple imprinting defects found by genetic analysis have been described. However, only two cases have been described with both genetic and clinical signs and symptoms of multiple diseases caused by imprinting defects. Case description: The girl in this case presented at the age of 6 months with morbid obesity (BMI +7.5 SDS) and a large umbilical hernia. Genetic analysis showed BWS (hypomethylation of the KCNQ1OT1 gene). Calcium homeostasis was normal and she had no signs of Albright Hereditary Osteodystrophy (AHO). At the age of 10 years she presented with fatigue and laboratory analyses showed marked hypocalcemia with signs of PTH resistance, but without evidence for AHO, thus suggesting pseudohypoparathyroidism type 1B (PHP1B). Consistent with this diagnosis, methylation analysis of the GNAS complex revealed hypomethylation (about 20%) of the GNAS exon 1A, NESPAS and GNASXL loci and hypermethylation (100% methylation) of NESP locus. Conclusions: Imprinting defects at several different loci can occur in some patients thus causing multiple different diseases. Symptoms of PHP1B may be absent at diagnosis of BWS, yet prolonged subclinical hypocalcemia and/or hyperphosphatemia can have negative consequences (e.g. intracerebral calcifications, myocardial dysfunction). We therefore suggest that patients with an imprinting disorder should be monitored for elevations in PTH and epigenetic analysis of the GNAS complex locus should be considered.
    Full-text · Article · Sep 2015 · The Journal of Clinical Endocrinology and Metabolism
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.
    Full-text · Article · Aug 2015 · European journal of human genetics: EJHG
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective Short stature caused by point mutations or deletions of the short stature homeobox (SHOX) gene (SHOX haploinsufficiency, SHI) is a registered indication for growth hormone (GH) treatment. Patients with a SHOX enhancer deletion (SED) have a similar phenotype, but their response to GH is unknown. It is uncertain if duplications of SHOX or its enhancer (SDUP) cause short stature. This study aimed to describe the clinical characteristics and growth response to GH treatment in patients with aberrations of SHOX and its enhancers. Design In this retrospective multi-center study (2002 to March 2014) clinical information was available from 130 patients (72 SHI, 44 SED, 14 SDUP) of whom 52 patients were treated with GH. We evaluated height, sitting height, arm span, dysmorphic features and indicators of the growth response to GH (delta height SDS, height velocity and Index of Responsiveness). Results Patients with SEDs showed similar height SDS to patients with SHI (-2.3 and -2.6, respectively, p=0.2), but they were less disproportionate (sitting height/height ratio SDS 2.0 vs. 3.1 (p<0.01), and extremities-trunk ratio 2.57 vs. 2.43 (p=0.03)). The first year growth response to GH treatment was significantly greater in prepubertal patients with SEDs than SHI. None of the patients with an SDUP was disproportionate and SDUP cosegregated poorly with short stature; their growth response to GH treatment (n=3) was similar to the other groups. Conclusions Patients with SEDs are equally short, but less disproportionate than patients with SHI, and show a greater response to GH.
    No preview · Article · Aug 2015 · European Journal of Endocrinology
  • [Show abstract] [Hide abstract]
    ABSTRACT: The RASopathies comprise a group of clinically overlapping developmental syndromes the common pathogenetic basis of which is dysregulated signal flow through the RAS-MAPK pathway. Mutations in several components or modifiers of the pathway have been identified in Noonan syndrome and related disorders. Over the past years copy number variants (CNVs) encompassing RAS pathway genes (PTPN11, RAF1, MEK2, or SHOC2) have been reported in children with developmental syndromes. These observations raised speculations that the associated phenotypes represent RASopathies, implying that the increased or reduced expression of the respective RAS pathway component and a consecutive dysregulation of RAS pathway signalling is responsible for the clinical picture. Herein, we present two individuals and three of their relatives harboring duplications of either 3p25.2 including the RAF1 locus or 19p13.3 including the MEK2 locus. Duplication carriers exhibited variable clinical phenotypes including non-specific facial dysmorphism, short stature, and learning difficulties. A careful review of the literature supported the impression that phenotypes associated with CNVs including RAS pathway genes commonly share non-specific symptoms with RASopathies, while the characteristic "gestalt" is lacking. Considering the known molecular pathogenesis of RASopathies, it is questionable that a modest increase in the expression of a functionally normal signaling component can mimic the effects of a qualitatively abnormal (hyperactive) mutant protein. We thus argue that current empirical and biological evidence is still insufficient to allow the conclusion that an altered copy number of a RAS pathway component is indeed the mechanism that is critical for the phenotype associated with CNVs including RASopathy genes. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    No preview · Article · May 2015 · American Journal of Medical Genetics Part A
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE: Mutations of the Fibroblast Growth Factor Receptor 3 (FGFR3) cause various forms of short stature, of which the least severe phenotype is hypochondroplasia, mainly characterized by disproportionate short stature. Testing for an FGFR3 mutation is currently not part of routine diagnostic testing in children with short stature without disproportion. DESIGN: A three generation family (A) with dominantly transmitted proportionate short stature was studied with whole exome sequencing to identify the causal gene mutation. Functional studies and protein modeling studies were performed to confirm the pathogenicity of the mutation found in FGFR3. We performed Sanger sequencing in a second family (B) with dominant proportionate short stature and identified a rare variant in FGFR3. METHODS: Exome sequencing and/or Sanger sequencing was performed, followed by functional studies using transfection of the mutant FGFR3 into cultured cells; homology modeling was used to construct a three-dimensional model of the two FGFR3 variants. RESULTS: A novel p.M528I mutation in FGFR3 was detected in Family A which segregates with short stature, and proved to be activating in vitro. In family B a rare variant (p.F384L) was found in FGFR3, which did not segregate with short stature and showed normal functionality in vitro compared to wild type. CONCLUSIONS: Proportionate short stature can be caused by a mutation in FGFR3. Sequencing of this gene can be considered in patients with short stature, especially when there is an autosomal dominant pattern of inheritance. However, functional studies and segregation studies should be performed before concluding that a variant is pathogenic.
    Full-text · Article · Mar 2015 · European Journal of Endocrinology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Context: PAPSS2 (PAPS synthase 2) provides the universal sulfate donor PAPS (3'-phospho-adenosine-5'-phosphosulfate) to all human sulfotransferases, including SULT2A1, responsible for sulfation of the crucial androgen precursor dehydroepiandrosterone (DHEA). Impaired DHEA sulfation is thought to increase the conversion of DHEA toward active androgens, a proposition supported by the previous report of a girl with inactivating PAPSS2 mutations who presented with low serum DHEA sulfate and androgen excess, clinically manifesting with premature pubarche and early-onset polycystic ovary syndrome. Patients and methods: We investigated a family harboring two novel PAPSS2 mutations, including two compound heterozygous brothers presenting with disproportionate short stature, low serum DHEA sulfate, but normal serum androgens. Patients and parents underwent a DHEA challenge test comprising frequent blood sampling and urine collection before and after 100 mg DHEA orally, with subsequent analysis of DHEA sulfation and androgen metabolism by mass spectrometry. The functional impact of the mutations was investigated in silico and in vitro. Results: We identified a novel PAPSS2 frameshift mutation, c.1371del, p.W462Cfs*3, resulting in complete disruption, and a novel missense mutation, c.809G>A, p.G270D, causing partial disruption of DHEA sulfation. Both patients and their mother, who was heterozygous for p.W462Cfs*3, showed increased 5α-reductase activity at baseline and significantly increased production of active androgens after DHEA intake. The mother had a history of oligomenorrhea and chronic anovulation that required clomiphene for ovulation induction. Conclusions: We provide direct in vivo evidence for the significant functional impact of mutant PAPSS2 on DHEA sulfation and androgen activation. Heterozygosity for PAPSS2 mutations can be associated with a phenotype resembling polycystic ovary syndrome.
    Full-text · Article · Jan 2015 · Journal of Clinical Endocrinology & Metabolism
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. We describe the identification of homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.892A>G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs∗22), c.298G>T (p.Ala100Ser), c.294T>G (p.Phe98Leu), c.269A>G (p.Glu90Gly), and c.700T>C (p.Tyr234His), all predicted to be disease causing. By using haplotype reconstruction we showed that the mutation c.298G>T is probably a founder mutation. Due to the spectrum of the amino acid changes, we suggest that loss of function in TGDS is the underlying mechanism of Catel-Manzke syndrome. TGDS (dTDP-D-glucose 4,6-dehydrogenase) is a conserved protein belonging to the SDR family and probably plays a role in nucleotide sugar metabolism.
    Full-text · Article · Dec 2014 · The American Journal of Human Genetics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.European Journal of Human Genetics advance online publication, 26 November 2014; doi:10.1038/ejhg.2014.253.
    Full-text · Article · Nov 2014 · European journal of human genetics: EJHG
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Most isodicentric (Xp) and (Xq) chromosomes occur as a mosaic with a 45,X cell line. Patients with a nonmosaic 46,X,idic(Xq) are rare. Cases: The first girl was referred at 13 years with a short stature and pubertal delay (M1, P2, A1). Her height was 141.6 cm (-3.1 SDS). Ovarian failure was present. The second girl was referred because of her short stature at 12.5 years. Her height was 142.2 cm (-2.4 SDS). She had spontaneous puberty (M3, P1, A1). Results: In both girls, conventional karyotyping of lymphocytes revealed an aberrant X chromosome consisting of twice the short arm and a small part of the long arm of the X chromosome [nonmosaic 46,X,psu idic(X)(q21.1)]. FISH analysis of the aberrant X chromosome showed the presence of two centromeres, two copies of the XIST gene and two copies of the SHOX gene. Conclusions: The presence of two XIST genes on the isodicentric X chromosome with Xq deletion indicates the inactivation of this chromosome. This inactivation also concerned the pseudoautosomal regions which caused haploinsufficiency of the SHOX genes. The girls were treated with growth hormones. The critical region (Xq23 to Xq28) for the ovarian function was deleted in both patients, but the gonadal function was variable. .
    No preview · Article · Apr 2014 · Hormone Research in Paediatrics
  • Sarina G. Kant · Mw. dr. Marie-José Walenkamp
    [Show abstract] [Hide abstract]
    ABSTRACT: Most of the variation in adult height is genetically controlled. The vast majority of the genetic factors that influence stature have a small effect. In the diagnostic workup for short stature it is only possible to analyze the genes that have a large effect on growth. However, before considering genetic analysis, it is crucial to characterize the growth retardation carefully by taking the patient history and the family history, a physical examination and sometimes radiological imaging. In this process it is important to pay attention to body proportions, dysmorphic features and/or congenital anomalies, and whether the growth retardation was already present at birth. In the case of disproportion (mostly short arms and legs compared to the trunk) a skeletal dysplasia is suspected, while in the coexistence of dysmorphic features and/or congenital anomalies (next to short stature) a syndromic form of growth retardation is more likely. When the patient is small for gestational age without catch-up growth, one has to consider anomalies of IGF-I or the IGF-I receptor. Reaching a diagnosis is important for prognosis and possible therapy.When no diagnosis can be made, it is recommended to consult experts from specialized outpatient clinics or (international) working groups. If still no diagnosis can be reached the advice is to see the child again in 2-3 years’ time and analyze the growth retardation once more, because new syndromes or additional insights in known disorders can be described by then, but also because of the ongoing development of molecular techniques.
    No preview · Article · Jan 2014 · Tijdschrift voor kindergeneeskunde
  • [Show abstract] [Hide abstract]
    ABSTRACT: Point mutations in PDE4D have been recently linked to acrodysostosis, an autosomal dominant disorder with skeletal dysplasia, severe brachydactyly, midfacial hypoplasia and intellectual disability. The purpose of the present study was to investigate clinical and cellular implications of different types of mutations in the PDE4D gene. We studied five acrodysostosis patients and three patients with gene dose imbalances involving PDE4D clinically and by whole exome sequencing, Sanger sequencing and array comparative hybridisation. To evaluate the functional consequences of the PDE4D changes, we used overexpression of mutated human PDE4D message and morpholino-based suppression of pde4d in zebrafish. We identified three novel and two previously described PDE4D point mutations in the acrodysostosis patients and two deletions and one duplication involving PDE4D in three patients suffering from an intellectual disability syndrome with low body mass index, long fingers, toes and arms, prominent nose and small chin. When comparing symptoms in patients with missense mutations and gene dose imbalances involving PDE4D, a mirror phenotype was observed. By comparing overexpression of human mutated transcripts with pde4d knockdown in zebrafish embryos, we could successfully assay the pathogenicity of the mutations. Our findings indicate that haploinsufficiency of PDE4D results in a novel intellectual disability syndrome, the 5q12.1-haploinsufficiency syndrome, with several opposing features compared with acrodysostosis that is caused by dominant negative mutations. In addition, our results expand the spectrum of PDE4D mutations underlying acrodysostosis and indicate that, in contrast to previous reports, patients with PDE4D mutations may have significant hormone resistance with consequent endocrine abnormalities.
    No preview · Article · Nov 2013 · Journal of Medical Genetics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: De novo germline variants in several components of the SWI/SNF-like BAF complex can cause Coffin–Siris syndrome (CSS), Nicolaides–Baraitser syndrome (NCBRS), and nonsyndromic intellectual disability. We screened 63 patients with a clinical diagnosis of CSS for these genes (ARID1A, ARID1B, SMARCA2, SMARCA4, SMARCB1, and SMARCE1) and identified pathogenic variants in 45 (71%) patients. We found a high proportion of variants in ARID1B (68%). All four pathogenic variants in ARID1A appeared to be mosaic. By using all variants from the Exome Variant Server as test data, we were able to classify variants in ARID1A, ARID1B, and SMARCB1 reliably as being pathogenic or nonpathogenic. For SMARCA2, SMARCA4, and SMARCE1 several variants in the EVS remained unclassified, underlining the importance of parental testing. We have entered all variant and clinical information in LOVD-powered databases to facilitate further genotype–phenotype correlations, as these will become increasingly important because of the uptake of targeted and untargeted next generation sequencing in diagnostics. The emerging phenotype–genotype correlation is that SMARCB1 patients have the most marked physical phenotype and severe cognitive and growth delay. The variability in phenotype seems most marked in ARID1A and ARID1B patients. Distal limbs anomalies are most marked in ARID1A patients and least in SMARCB1 patients. Numbers are small however, and larger series are needed to confirm this correlation.
    Full-text · Article · Nov 2013 · Human Mutation
  • Source

    Full-text · Dataset · Oct 2013
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty-three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes.European Journal of Human Genetics advance online publication, 25 September 2013; doi:10.1038/ejhg.2013.203.
    Full-text · Article · Sep 2013 · European journal of human genetics: EJHG
  • [Show abstract] [Hide abstract]
    ABSTRACT: BackgroundC-type natriuretic peptide (CNP)/natriuretic peptide receptor 2 (NPR2) signalling is essential for long bone growth. Enhanced CNP production caused by chromosomal translocations results in tall stature, a Marfanoid phenotype and skeletal abnormalities. A similar phenotype was described in a family with an activating NPR2 mutation within the guanylyl cyclase domain.CaseHere we describe an extremely tall male without skeletal deformities, with a novel NPR2 mutation (p.Arg655Cys) located in the kinase homology domain (KHD).Objectives To investigate the functional and structural effects of the NPR2 mutation.Methods Guanylyl cyclase activities of wildtype vs mutant NPR2 were analyzed in transfected HEK 293 cells and in skin fibroblasts. The former were also used to study possible interactions between both isoforms. Homology modeling was performed to understand the molecular impact of the mutation.ResultsCNP stimulated cGMP production by the mutant NPR2 was markedly increased in patient skin fibroblasts and transfected HEK293 cells. The stimulatory effects of ATP on CNP-dependent guanylyl cyclase activity were augmented, suggesting that this novel mutation enhances both the responsiveness of NPR2 to CNP and its allosteric modulation/stabilisation by ATP. Co-immunoprecipitation showed that wildtype and mutant NPR2 can form stable heterodimers, suggesting a dominant positive effect. In accordance with augmented endogenous receptor activity, plasma NTproCNP (a marker of CNP production in tissues) was reduced in the proband.Conclusions We report the first activating mutation within the KHD of NPR2, resulting in extremely tall stature. Our observations emphasize the important role of this domain in the regulation of guanylyl cyclase activity and bone growth in response to CNP.
    No preview · Article · Sep 2013 · The Journal of Clinical Endocrinology and Metabolism

  • No preview · Article · Aug 2013 · BMC pharmacology & toxicology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype--genotype correlation has been lacking. Methods: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). Results and conclusions: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.
    Full-text · Article · May 2013 · Journal of Medical Genetics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome. Methods and results Clinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from 2 to 52 years. The facial phenotype and expressive language impairments were defining features within the group. Height measurements were typically between minus two and minus four standard deviations, with occipitofrontal circumferences usually within the average range. Thirty-three of the subjects (63%) had at least one major anomaly requiring medical intervention. We did not observe any specific phenotype-genotype correlations. This large cohort of individuals with molecularly confirmed FHS has allowed us to better delineate the clinical features of this rare but classic genetic syndrome, thereby facilitating the development of management protocols.
    Full-text · Article · Apr 2013 · Orphanet Journal of Rare Diseases
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Context. Leri–Weill dyschondrosteosis is a clinically variable skeletal dysplasia, caused by SHOX deletion or mutations, or a deletion of enhancer sequences in the 3’-flanking region. Recently, a 47.5 kb recurrent PAR1 deletion downstream of SHOX was reported, but its frequency and clinical importance are still unknown. Objective. This study aims to compare the clinical features of different sizes of deletions in the 3’-flanking SHOX region in order to determine the relevance of the regulatory sequences in this region. Design. We collected DNA from 28 families with deletions in the 3’-PAR1 region. Clinical data were available from 23 index patients and 21 relatives. Results. In 9 families (20 individuals) a large deletion ( ∼ 200–900 kb) was found and in 19 families (35 individuals) a small deletion was demonstrated, equal to the recently described 47.5 kb PAR1 deletion. Median height SDS, sitting height/height ratio SDS and the presence of Madelung deformity in patients with the 47.5 kb deletion were not significantly different from patients with larger deletions. The index patients had a median height SDS which was slightly lower than in their affected family members (p = 0.08). No significant differences were observed between male and female patients. Conclusions. The phenotype of patients with deletions in the 3’-PAR1 region is remarkably variable. Height, sitting height/height ratio and the presence of Madelung deformity were not significantly different between patients with the 47.5 kb recurrent PAR1 deletion and those with larger deletions, suggesting that this enhancer plays an important role in SHOX expression.
    Full-text · Article · Feb 2013 · PeerJ

Publication Stats

2k Citations
366.52 Total Impact Points

Institutions

  • 2008-2015
    • Leiden University
      Leyden, South Holland, Netherlands
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      Erlangen, Bavaria, Germany
  • 2001-2014
    • Leiden University Medical Centre
      • • Department of Clinical Genetics
      • • Department of Pediatrics
      Leyden, South Holland, Netherlands
  • 2007
    • St. James University
      Сент-Джеймс, New York, United States