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2.
Genet Med ; 21(9): 2059-2069, 2019 09.
Article in English | MEDLINE | ID: mdl-30923367

ABSTRACT

PURPOSE: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro. METHODS: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs. RESULTS: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001). CONCLUSION: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.


Subject(s)
DNA-Binding Proteins/genetics , Developmental Disabilities/genetics , Intellectual Disability/genetics , Microcephaly/genetics , Transcription Factors/genetics , Adolescent , Adult , Alleles , Autistic Disorder/genetics , Autistic Disorder/pathology , Child , Child, Preschool , Developmental Disabilities/pathology , Exome/genetics , Female , Genetic Association Studies , Humans , Intellectual Disability/pathology , Language Development Disorders/genetics , Language Development Disorders/pathology , Male , Microcephaly/pathology , Mutation, Missense/genetics , Young Adult
4.
J Clin Endocrinol Metab ; 102(12): 4534-4540, 2017 12 01.
Article in English | MEDLINE | ID: mdl-29040582

ABSTRACT

Context: Heterozygous pathogenic germline variants in CDC73 predispose to the development of primary hyperparathyroidism (pHPT) and, less frequently, ossifying fibroma of the jaw and renal and uterine tumors. Clinical information on CDC73-related disorders has so far been limited to small case series. Objective: To assess the clinical manifestations and penetrance in CDC73-related disorders and to improve case detection in pHPT. Design: Nationwide retrospective Dutch cohort study. Setting: Tertiary referral center. Patients: We studied 89 patients with pHPT referred for germline CDC73 analysis and 43 subsequently tested relatives who proved to be mutation carriers. Investigation: Germline CDC73 mutation analysis. Mean Outcome: CDC73 mutation detection yield, referral rate, and CDC73-related disease penetrance. Results: Pathogenic germline CDC73 variants were identified in 11 of the 89 referred pHPT patients (12.4%), with (suspected) hyperparathyroidism-jaw tumor (HPT-JT) syndrome (n = 3), familial isolated pHPT (n = 5), apparently sporadic parathyroid carcinoma (n = 2), and apparently sporadic parathyroid adenoma (n = 1). The estimated penetrance of CDC73-related disorders was 65% at age 50 years (95% confidence interval, 48% to 82%) in 43 nonindex mutation carriers. Conclusions: Germline CDC73 analysis is recommended in individuals with (suspected) HPT-JT syndrome, familial isolated pHPT, atypical or malignant parathyroid histology, and young individuals with pHPT. These criteria would increase germline CDC73 mutation detection, enabling optimal clinical management of pHPT as well as genetic counseling and surveillance for family members at risk for developing CDC73-related disorders.


Subject(s)
Hyperparathyroidism, Primary/genetics , Hyperparathyroidism, Primary/physiopathology , Tumor Suppressor Proteins/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Cohort Studies , Female , Germ-Line Mutation , Heterozygote , Humans , Hyperparathyroidism, Primary/pathology , Jaw Neoplasms/genetics , Jaw Neoplasms/pathology , Male , Middle Aged , Mutation/genetics , Netherlands , Parathyroid Neoplasms/genetics , Parathyroid Neoplasms/pathology , Penetrance , Retrospective Studies , Young Adult
5.
Am J Hum Genet ; 100(2): 281-296, 2017 02 02.
Article in English | MEDLINE | ID: mdl-28132690

ABSTRACT

EXTL3 regulates the biosynthesis of heparan sulfate (HS), important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs). By whole-exome sequencing, we identified homozygous missense mutations c.1382C>T, c.1537C>T, c.1970A>G, and c.2008T>G in EXTL3 in nine affected individuals from five unrelated families. Notably, we found the identical homozygous missense mutation c.1382C>T (p.Pro461Leu) in four affected individuals from two unrelated families. Affected individuals presented with variable skeletal abnormalities and neurodevelopmental defects. Severe combined immunodeficiency (SCID) with a complete absence of T cells was observed in three families. EXTL3 was most abundant in hematopoietic stem cells and early progenitor T cells, which is in line with a SCID phenotype at the level of early T cell development in the thymus. To provide further support for the hypothesis that mutations in EXTL3 cause a neuro-immuno-skeletal dysplasia syndrome, and to gain insight into the pathogenesis of the disorder, we analyzed the localization of EXTL3 in fibroblasts derived from affected individuals and determined glycosaminoglycan concentrations in these cells as well as in urine and blood. We observed abnormal glycosaminoglycan concentrations and increased concentrations of the non-sulfated chondroitin disaccharide D0a0 and the disaccharide D0a4 in serum and urine of all analyzed affected individuals. In summary, we show that biallelic mutations in EXTL3 disturb glycosaminoglycan synthesis and thus lead to a recognizable syndrome characterized by variable expression of skeletal, neurological, and immunological abnormalities.


Subject(s)
Musculoskeletal Abnormalities/genetics , N-Acetylglucosaminyltransferases/genetics , Osteochondrodysplasias/genetics , Alleles , Cell Line , Cell Line, Tumor , Chondroitin/blood , Chondroitin/urine , DNA Copy Number Variations , Genome-Wide Association Study , Glycosaminoglycans/metabolism , Humans , Musculoskeletal Abnormalities/diagnosis , Mutation, Missense , Osteochondrodysplasias/diagnosis , Severe Combined Immunodeficiency/diagnosis , Severe Combined Immunodeficiency/genetics
6.
Birth Defects Res A Clin Mol Teratol ; 106(7): 573-9, 2016 Jul.
Article in English | MEDLINE | ID: mdl-26991659

ABSTRACT

BACKGROUND: Recent studies reported an association between prenatal propylthiouracil exposure and birth defects, including abnormal arrangement across the left-right body axis, suggesting an association with heterotaxy syndrome. METHODS: This case-control and case-finding study used data from 1981 to 2013 from the EUROCAT birth defect registry in the Northern Netherlands. First, we explored prenatal exposures in heterotaxy syndrome (cases) and Down syndrome (controls). Second, we describe the specific birth defects in offspring of mothers using propylthiouracil (PTU) prenatally. RESULTS: A total of 66 cases with heterotaxy syndrome (incidence 12.1 per 100,000 pregnancies) and 783 controls with Down syndrome (143.3 per 100,000 pregnancies) were studied. No differences in intoxication use during pregnancy were found between cases and controls, including smoking (28.0% vs. 22.7%; p = 0.40), alcohol (14.0% vs. 26.9%; p = 0.052), and recreational drugs (0 vs. 0.3%; p = 1.00). We found an association between heterotaxy syndrome and prenatal drug exposure to follitropin-alfa (5.6% vs. 1.1%; p = 0.04), and drugs used in nicotine dependence (3.7% vs. 0.2%; p = 0.02). Five mothers used PTU during pregnancy and gave birth to a child with trisomy 18, renal abnormalities, or hypospadias and cardiac defects. CONCLUSION: This study identified follitropin-alfa and drugs used in nicotine dependence as possible teratogens of heterotaxy syndrome. Our data suggest the possibility that there is an increased risk of birth defects (including renal, urological, and cardiac abnormalities) in children born among mothers taking PTU prenatally, but not for heterotaxy syndrome. Birth Defects Research (Part A) 106:573-579, 2016. © 2016 Wiley Periodicals, Inc.


Subject(s)
Follicle Stimulating Hormone, Human/adverse effects , Prenatal Exposure Delayed Effects , Registries , Adult , Alcohol Drinking/adverse effects , Case-Control Studies , Down Syndrome/chemically induced , Down Syndrome/epidemiology , Female , Follicle Stimulating Hormone, Human/administration & dosage , Heterotaxy Syndrome/chemically induced , Heterotaxy Syndrome/epidemiology , Humans , Illicit Drugs/adverse effects , Netherlands/epidemiology , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Prenatal Exposure Delayed Effects/epidemiology , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Smoking/adverse effects
7.
Am J Hum Genet ; 98(1): 202-9, 2016 Jan 07.
Article in English | MEDLINE | ID: mdl-26708751

ABSTRACT

Ion channel proteins are required for both the establishment of resting membrane potentials and the generation of action potentials. Hundreds of mutations in genes encoding voltage-gated ion channels responsible for action potential generation have been found to cause severe neurological diseases. In contrast, the roles of voltage-independent "leak" channels, important for the establishment and maintenance of resting membrane potentials upon which action potentials are generated, are not well established in human disease. UNC80 is a large component of the NALCN sodium-leak channel complex that regulates the basal excitability of the nervous system. Loss-of-function mutations of NALCN cause infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF). We report four individuals from three unrelated families who have homozygous missense or compound heterozygous truncating mutations in UNC80 and persistent hypotonia, encephalopathy, growth failure, and severe intellectual disability. Compared to control cells, HEK293T cells transfected with an expression plasmid containing the c.5098C>T (p.Pro1700Ser) UNC80 mutation found in one individual showed markedly decreased NALCN channel currents. Our findings demonstrate the fundamental significance of UNC80 and basal ionic conductance to human health.


Subject(s)
Alleles , Brain Diseases/genetics , Carrier Proteins/genetics , Growth Disorders/genetics , Intellectual Disability/genetics , Membrane Proteins/genetics , Muscle Hypotonia/genetics , Mutation , Adolescent , Child , Child, Preschool , Female , Humans , Severity of Illness Index
9.
Eur J Med Genet ; 58(5): 279-92, 2015 May.
Article in English | MEDLINE | ID: mdl-25792522

ABSTRACT

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities, and subdivided in TRPS I, caused by mutations in TRPS1, and TRPS II, caused by a contiguous gene deletion affecting (amongst others) TRPS1 and EXT1. We performed a collaborative international study to delineate phenotype, natural history, variability, and genotype-phenotype correlations in more detail. We gathered information on 103 cytogenetically or molecularly confirmed affected individuals. TRPS I was present in 85 individuals (22 missense mutations, 62 other mutations), TRPS II in 14, and in 5 it remained uncertain whether TRPS1 was partially or completely deleted. Main features defining the facial phenotype include fine and sparse hair, thick and broad eyebrows, especially the medial portion, a broad nasal ridge and tip, underdeveloped nasal alae, and a broad columella. The facial manifestations in patients with TRPS I and TRPS II do not show a significant difference. In the limbs the main findings are short hands and feet, hypermobility, and a tendency for isolated metacarpals and metatarsals to be shortened. Nails of fingers and toes are typically thin and dystrophic. The radiological hallmark are the cone-shaped epiphyses and in TRPS II multiple exostoses. Osteopenia is common in both, as is reduced linear growth, both prenatally and postnatally. Variability for all findings, also within a single family, can be marked. Morbidity mostly concerns joint problems, manifesting in increased or decreased mobility, pain and in a minority an increased fracture rate. The hips can be markedly affected at a (very) young age. Intellectual disability is uncommon in TRPS I and, if present, usually mild. In TRPS II intellectual disability is present in most but not all, and again typically mild to moderate in severity. Missense mutations are located exclusively in exon 6 and 7 of TRPS1. Other mutations are located anywhere in exons 4-7. Whole gene deletions are common but have variable breakpoints. Most of the phenotype in patients with TRPS II is explained by the deletion of TRPS1 and EXT1, but haploinsufficiency of RAD21 is also likely to contribute. Genotype-phenotype studies showed that mutations located in exon 6 may have somewhat more pronounced facial characteristics and more marked shortening of hands and feet compared to mutations located elsewhere in TRPS1, but numbers are too small to allow firm conclusions.


Subject(s)
Abnormalities, Multiple/genetics , DNA-Binding Proteins/genetics , Langer-Giedion Syndrome/genetics , Transcription Factors/genetics , Abnormalities, Multiple/pathology , Adolescent , Adult , Aged , Child , Child, Preschool , Female , Genetic Association Studies , Humans , Infant , Langer-Giedion Syndrome/pathology , Male , Middle Aged , Mutation, Missense , Repressor Proteins , Young Adult
10.
Hum Genet ; 133(9): 1117-25, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24889830

ABSTRACT

Sequencing technology is increasingly demonstrating the impact of genomic copy number variation (CNV) on phenotypes. Opposing variation in growth, head size, cognition and behaviour is known to result from deletions and reciprocal duplications of some genomic regions. We propose normative inversion of face shape, opposing difference from a matched norm, as a basis for investigating the effects of gene dosage on craniofacial development. We use dense surface modelling techniques to match any face (or part of a face) to a facial norm of unaffected individuals of matched age, sex and ethnicity and then we reverse the individual's face shape differences from the matched norm to produce the normative inversion. We demonstrate for five genomic regions, 4p16.3, 7q11.23, 11p15, 16p13.3 and 17p11.2, that such inversion for individuals with a duplication or (epi)-mutation produces facial forms remarkably similar to those associated with a deletion or opposite (epi-)mutation of the same region, and vice versa. The ability to visualise and quantify face shape effects of gene dosage is of major benefit for determining whether a CNV is the cause of the phenotype of an individual and for predicting reciprocal consequences. It enables face shape to be used as a relatively simple and inexpensive functional analysis of the gene(s) involved.


Subject(s)
Chromosome Disorders/genetics , Face/anatomy & histology , Gene Dosage , Adolescent , Adult , Black People/genetics , Case-Control Studies , Child , Child, Preschool , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 16 , Chromosomes, Human, Pair 17 , Chromosomes, Human, Pair 4 , Chromosomes, Human, Pair 7 , DNA Copy Number Variations , Face/abnormalities , Female , Gene Duplication , Humans , Imaging, Three-Dimensional , Male , Phenotype , Sequence Deletion , White People/genetics
11.
Neuromuscul Disord ; 23(6): 461-8, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23566544

ABSTRACT

Spinal muscular atrophy with respiratory distress type 1 is an autosomal recessive disorder with early respiratory difficulties, distal muscle weakness, and contractures leading to foot deformities as the most striking clinical symptoms. Mutations of the gene encoding the immunoglobulin heavy chain µ-binding protein 2, mapped on chromosome 11q13, are the cause of the disease. We present the clinical and mutational characteristics of ten patients in the Netherlands who showed considerable clinical variability; they carried six novel mutations, including a deletion of exon 2. However, there were no clear phenotype-genotype correlations.


Subject(s)
Muscle Weakness/genetics , Muscular Atrophy, Spinal/genetics , Mutation/genetics , Respiratory Distress Syndrome, Newborn/genetics , Spinal Muscular Atrophies of Childhood/genetics , Child, Preschool , Chromosome Mapping , Female , Genetic Predisposition to Disease/genetics , Humans , Infant , Male , Muscular Atrophy, Spinal/diagnosis , Netherlands , Respiratory Distress Syndrome, Newborn/diagnosis , Spinal Muscular Atrophies of Childhood/diagnosis , Transcription Factors/genetics
13.
Eur J Hum Genet ; 19(5): 513-9, 2011 May.
Article in English | MEDLINE | ID: mdl-21368916

ABSTRACT

Bohring-Opitz syndrome (BOS) is a rare congenital disorder of unknown etiology diagnosed on the basis of distinctive clinical features. We suggest diagnostic criteria for this condition, describe ten previously unreported patients, and update the natural history of four previously reported patients. This is the largest series reported to date, providing a unique opportunity to document the key clinical features and course through childhood. Investigations undertaken to try and elucidate the underlying pathogenesis of BOS using array comparative genomic hybridization and tandem mass spectrometry of cholesterol precursors did not show any pathogenic changes responsible.


Subject(s)
Cholesterol/biosynthesis , Child, Preschool , Comparative Genomic Hybridization , Craniosynostoses/genetics , Craniosynostoses/pathology , Craniosynostoses/physiopathology , Female , Humans , Infant , Intellectual Disability/genetics , Intellectual Disability/pathology , Intellectual Disability/physiopathology , Male
14.
J Neurol Neurosurg Psychiatry ; 82(8): 850-2, 2011 Aug.
Article in English | MEDLINE | ID: mdl-20551479

ABSTRACT

BACKGROUND: Spinal muscular atrophy (SMA) is caused by the homozygous deletion of the survival motor neuron (SMN)1 gene. The nearly identical SMN2 gene produces small amounts of full-length mRNA and functional SMN protein, due to a point mutation in a critical splicing site. Increasing SMN protein production by histone deacetylase inhibiting drugs such as valproic acid (VPA) is an experimental treatment strategy for SMA. OBJECTIVE: To investigate whether an SMN-specific ELISA could detect changes in SMN protein expression in peripheral blood mononuclear cells (PBMCs) after treatment with VPA. METHODS: The authors developed a sensitive SMN-specific ELISA. Six patients with SMA types 2 and 3 participated in the study. Recombinant SMN calibration curves were used to calculate SMN protein levels in PBMCs before and after 4 months of VPA treatment. RESULTS: The SMN ELISA was able to detect small differences in SMN protein concentrations, and differences in SMN protein levels in Epstein-Barr virus immortalised lymphocyte cell lines from SMA type 1 and 2 patients, carriers and healthy individuals (p<0.05). The mean SMN protein level in PBMCs from SMA patients was 22% (SD 15%) of the value in a healthy control. VPA treatment resulted in significantly increased SMN protein levels in five out of six SMA patients compared with baseline values (p<0.05), but did not restore SMN levels to normal values. CONCLUSIONS: SMN protein quantification by this SMN ELISA is a useful additional tool for evaluating the effects of experimental treatment in SMA.


Subject(s)
Enzyme-Linked Immunosorbent Assay , GABA Agents/pharmacology , Spinal Muscular Atrophies of Childhood/drug therapy , Spinal Muscular Atrophies of Childhood/metabolism , Survival of Motor Neuron 1 Protein/metabolism , Valproic Acid/pharmacology , Adolescent , Child , Child, Preschool , Female , Humans , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Male , Treatment Outcome
15.
Brain ; 130(Pt 9): 2258-66, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17690130

ABSTRACT

Four unrelated children are described with an identical brainstem and cerebellar malformation on MRI. The key findings are: vermal hypoplasia, subtotal absence of middle cerebellar peduncles, flattened ventral pons, vaulted pontine tegmentum, molar tooth aspect of the pontomesencephalic junction and absent inferior olivary prominence. Peripheral hearing impairment is present in all. Variable findings are: horizontal gaze palsy (1/4), impaired swallowing (2/4), facial palsy (3/4), bilateral sensory trigeminal nerve involvement (1/4), ataxia (2/4). Bony vertebral anomalies are found in 3/4. Additional MR studies in one patient using diffusion tensor imaging (DTI) with colour coding and fibre tracking revealed an ectopic transverse fibre bundle at the site of the pontine tegmentum and complete absence of transverse fibres in the ventral pons. The combined findings indicate an embryonic defect in axonal growth and guidance. Phenotypic analogy to mice with homozygous inactivation of Ntn1 encoding the secreted axonal guidance protein netrin1, or Dcc encoding its receptor Deleted in Colorectal Cancer led us to perform sequence analysis of NTN1 and DCC in all the patients. No pathogenic mutations were found. For the purpose of description the name 'pontine tegmental cap dysplasia' (PTCD) is proposed for the present malformation, referring to its most distinguishing feature on routine MRI.


Subject(s)
Axons/pathology , Cerebellum/abnormalities , Pons/abnormalities , Brain/pathology , Cerebellum/pathology , Child, Preschool , DNA Mutational Analysis , Female , Genes, DCC/genetics , Humans , Infant , Magnetic Resonance Imaging , Male , Nerve Growth Factors/genetics , Netrin-1 , Pons/pathology , Syndrome , Tumor Suppressor Proteins/genetics
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