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1.
Am J Hum Genet ; 105(5): 933-946, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31607427

RESUMO

Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a "phenotype first" approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands.

2.
Genet Med ; 21(9): 2059-2069, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30923367

RESUMO

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.

3.
Science ; 362(6419): 1161-1164, 2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30409806

RESUMO

We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.

4.
5.
Eur J Hum Genet ; 26(11): 1611-1622, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30006632

RESUMO

Acrodysostosis (MIM 101800) is a dominantly inherited condition associating (1) skeletal features (short stature, facial dysostosis, and brachydactyly with cone-shaped epiphyses), (2) resistance to hormones and (3) possible intellectual disability. Acroscyphodysplasia (MIM 250215) is characterized by growth retardation, brachydactyly, and knee epiphyses embedded in cup-shaped metaphyses. We and others have identified PDE4D or PRKAR1A variants in acrodysostosis; PDE4D variants have been reported in three cases of acroscyphodysplasia. Our study aimed at reviewing the clinical and molecular findings in a cohort of 27 acrodysostosis and 5 acroscyphodysplasia cases. Among the acrodysostosis cases, we identified 9 heterozygous de novo PRKAR1A variants and 11 heterozygous PDE4D variants. The 7 patients without variants presented with symptoms of acrodysostosis (brachydactyly and cone-shaped epiphyses), but none had the characteristic facial dysostosis. In the acroscyphodysplasia cases, we identified 2 PDE4D variants. For 2 of the 3 negative cases, medical records revealed early severe infection, which has been described in some reports of acroscyphodysplasia. Subdividing our series of acrodysostosis based on the disease-causing gene, we confirmed genotype-phenotype correlations. Hormone resistance was consistently observed in patients carrying PRKAR1A variants, whereas no hormone resistance was observed in 9 patients with PDE4D variants. All patients with PDE4D variants shared characteristic facial features (midface hypoplasia with nasal hypoplasia) and some degree of intellectual disability. Our findings of PDE4D variants in two cases of acroscyphodysplasia support that PDE4D may be responsible for this severe skeletal dysplasia. We eventually emphasize the importance of some specific assessments in the long-term follow up, including cardiovascular and thromboembolic risk factors.

6.
Hum Mutat ; 39(9): 1246-1261, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29924900

RESUMO

Adams-Oliver syndrome (AOS) is a rare developmental disorder, characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance. Data on the frequency and distribution of mutations in large cohorts are currently limited. The purpose of this study was therefore to comprehensively examine the genetic architecture of AOS in an extensive cohort. Molecular diagnostic screening of 194 AOS/ACC/TTLD probands/families was conducted using next-generation and/or capillary sequencing analyses. In total, we identified 63 (likely) pathogenic mutations, comprising 56 distinct and 22 novel mutations, providing a molecular diagnosis in 30% of patients. Taken together with previous reports, these findings bring the total number of reported disease variants to 63, with a diagnostic yield of 36% in familial cases. NOTCH1 is the major contributor, underlying 10% of AOS/ACC/TTLD cases, with DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort. We confirm the relevance of genetic screening across the AOS/ACC/TTLD spectrum, highlighting preliminary but important genotype-phenotype correlations. This cohort offers potential for further gene identification to address missing heritability.

7.
Eur J Hum Genet ; 26(9): 1306-1311, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29907757

RESUMO

Trio based whole exome sequencing via the Deciphering Developmental Disorders (DDD) study has identified three individuals with de novo frameshift variants in the Suppressor of Variegation, Enhancer of Zeste, and Trithorax (SET) gene. Variants in the SET gene have not previously been recognised to be associated with human developmental disorders. Here we report detailed phenotypic information and propose that SET is a new Intellectual Disability/Developmental Delay (ID/DD) gene.

8.
Am J Med Genet A ; 176(5): 1108-1114, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29383814

RESUMO

Variants in the Protein Kinase CK2 alpha subunit, encoding the CSNK2A1 gene, have previously been reported in children with an intellectual disability and dysmorphic facial features syndrome: now termed the Okur-Chung neurodevelopmental syndrome. More recently, through trio-based exome sequencing undertaken by the Deciphering Developmental Disorders Study (DDD study), a further 11 children with de novo CSNK2A1 variants have been identified. We have undertaken detailed phenotyping of these patients. Consistent with previously reported patients, patients in this series had apparent intellectual disability, swallowing difficulties, and hypotonia. While there are some shared facial characteristics, the gestalt is neither consistent nor readily recognized. Congenital heart abnormalities were identified in nearly 30% of the patients, representing a newly recognized CSNK2A1 clinical association. Based upon the clinical findings from this study and the previously reported patients, we suggest an initial approach to the management of patients with this recently described intellectual disability syndrome.

10.
Mol Genet Genomic Med ; 5(5): 495-507, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28944233

RESUMO

BACKGROUND: Syntaxin-binding protein 1, encoded by STXBP1, is highly expressed in the brain and involved in fusing synaptic vesicles with the plasma membrane. Studies have shown that pathogenic loss-of-function variants in this gene result in various types of epilepsies, mostly beginning early in life. We were interested to model pathogenic missense variants on the protein structure to investigate the mechanism of pathogenicity and genotype-phenotype correlations. METHODS: We report 11 patients with pathogenic de novo mutations in STXBP1 identified in the first 4293 trios of the Deciphering Developmental Disorder (DDD) study, including six missense variants. We analyzed the structural locations of the pathogenic missense variants from this study and the literature, as well as population missense variants extracted from Exome Aggregation Consortium (ExAC). RESULTS: Pathogenic variants are significantly more likely to occur at highly conserved locations than population variants, and be buried inside the protein domain. Pathogenic mutations are also more likely to destabilize the domain structure compared with population variants, increasing the proportion of (partially) unfolded domains that are prone to aggregation or degradation. We were unable to detect any genotype-phenotype correlation, but unlike previously reported cases, most of the DDD patients with STXBP1 pathogenic variants did not present with very early-onset or severe epilepsy and encephalopathy, though all have developmental delay with intellectual disability and most display behavioral problems and suffered seizures in later childhood. CONCLUSION: Variants across STXBP1 that cause loss of function can result in severe intellectual disability with or without seizures, consistent with a haploinsufficiency mechanism. Pathogenic missense mutations act through destabilization of the protein domain, making it prone to aggregation or degradation. The presence or absence of early seizures may reflect ascertainment bias in the literature as well as the broad recruitment strategy of the DDD study.

11.
Neurol Genet ; 2(6): e115, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27830185

RESUMO

Voltage-gated sodium channels (Navs) are mainstays of neuronal function, and mutations in the genes encoding CNS Navs (Nav1.1 [SCN1A], Nav1.2 [SCN2A], Nav1.3 [SCN3A], and Nav1.6 [SCN8A]) are causes of some of the most common and severe genetic epilepsies and epileptic encephalopathies (EE).1 Fibroblast-growth-factor homologous factors (FHFs) compose a family of 4 proteins that interact with the C-terminal tails of Navs to modulate the channels' fast, and long-term, inactivations.2FHF2 mutation is a rare cause of generalized epilepsy with febrile seizures plus (GEFS+).3 Recently, a de novo FHF1 mutation (p.R52H) was reported in early-onset EE in 2 siblings.4 We report 3 patients from unrelated families with the same FHF1 p.R52H mutation. The 5 cases together frame the FHF1 R52H EE from infancy to adulthood. As discussed below, this gain-of-function disease may be amenable to personalized therapy.

12.
PLoS One ; 11(4): e0153757, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27124303

RESUMO

We report molecular genetic analysis of 42 affected individuals referred with a diagnosis of aniridia who previously screened as negative for intragenic PAX6 mutations. Of these 42, the diagnoses were 31 individuals with aniridia and 11 individuals referred with a diagnosis of Gillespie syndrome (iris hypoplasia, ataxia and mild to moderate developmental delay). Array-based comparative genomic hybridization identified six whole gene deletions: four encompassing PAX6 and two encompassing FOXC1. Six deletions with plausible cis-regulatory effects were identified: five that were 3' (telomeric) to PAX6 and one within a gene desert 5' (telomeric) to PITX2. Sequence analysis of the FOXC1 and PITX2 coding regions identified two plausibly pathogenic de novo FOXC1 missense mutations (p.Pro79Thr and p.Leu101Pro). No intragenic mutations were detected in PITX2. FISH mapping in an individual with Gillespie-like syndrome with an apparently balanced X;11 reciprocal translocation revealed disruption of a gene at each breakpoint: ARHGAP6 on the X chromosome and PHF21A on chromosome 11. In the other individuals with Gillespie syndrome no mutations were identified in either of these genes, or in HCCS which lies close to the Xp breakpoint. Disruption of PHF21A has previously been implicated in the causation of intellectual disability (but not aniridia). Plausibly causative mutations were identified in 15 out of 42 individuals (12/32 aniridia; 3/11 Gillespie syndrome). Fourteen of these mutations presented in the known aniridia genes; PAX6, FOXC1 and PITX2. The large number of individuals in the cohort with no mutation identified suggests greater locus heterogeneity may exist in both isolated and syndromic aniridia than was previously appreciated.


Assuntos
Aniridia/genética , Ataxia Cerebelar/genética , Deficiência Intelectual/genética , Fator de Transcrição PAX6/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos X/genética , Hibridização Genômica Comparativa/métodos , Feminino , Fatores de Transcrição Forkhead/genética , Proteínas Ativadoras de GTPase/genética , Testes Genéticos/métodos , Histona Desacetilases/genética , Proteínas de Homeodomínio/genética , Humanos , Masculino , Mutação/genética , Fatores de Transcrição/genética
13.
Hum Mol Genet ; 25(5): 927-35, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26740553

RESUMO

We present a generic, multidisciplinary approach for improving our understanding of novel missense variants in recently discovered disease genes exhibiting genetic heterogeneity, by combining clinical and population genetics with protein structural analysis. Using six new de novo missense diagnoses in TBL1XR1 from the Deciphering Developmental Disorders study, together with population variation data, we show that the ß-propeller structure of the ubiquitous WD40 domain provides a convincing way to discriminate between pathogenic and benign variation. Children with likely pathogenic mutations in this gene have severely delayed language development, often accompanied by intellectual disability, autism, dysmorphology and gastrointestinal problems. Amino acids affected by likely pathogenic missense mutations are either crucial for the stability of the fold, forming part of a highly conserved symmetrically repeating hydrogen-bonded tetrad, or located at the top face of the ß-propeller, where 'hotspot' residues affect the binding of ß-catenin to the TBLR1 protein. In contrast, those altered by population variation are significantly less likely to be spatially clustered towards the top face or to be at buried or highly conserved residues. This result is useful not only for interpreting benign and pathogenic missense variants in this gene, but also in other WD40 domains, many of which are associated with disease.


Assuntos
Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Heterogeneidade Genética , Mutação de Sentido Incorreto , Proteínas Nucleares/química , Receptores Citoplasmáticos e Nucleares/química , Proteínas Repressoras/química , beta Catenina/química , Sequência de Aminoácidos , Criança , Pré-Escolar , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Feminino , Expressão Gênica , Genética Populacional , Humanos , Ligações de Hidrogênio , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Prognóstico , Ligação Proteica , Domínios Proteicos , Estrutura Secundária de Proteína , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Alinhamento de Sequência , beta Catenina/genética , beta Catenina/metabolismo
14.
Eur J Hum Genet ; 24(5): 652-9, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26306646

RESUMO

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.


Assuntos
Anormalidades Múltiplas/diagnóstico , Deficiência Intelectual/diagnóstico , Proteínas Nucleares/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade
15.
BMJ Case Rep ; 20152015 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-26276849

RESUMO

A male infant at 36 weeks gestation was born by section. At 20 weeks of gestation, congenital diaphragmatic hernia and sacrococcygeal teratoma had been seen on ultrasound. At birth, the infant had features suggestive of Cornelia de Lange syndrome (CdLS). He remained hypoxic despite aggressive ventilatory manoeuvres and was palliated. At postmortem, the lungs were hypoplastic. In CdLS, mutations in NIPBL are found in around 50% of cases. Mutation analysis, including multiplex ligation dependent probe amplification of the NIPBL gene from the DNA extracted from peripheral blood lymphocytes was negative, but microarray comparative genomic hybridisation on DNA from skin fibroblast showed a 0.13Mb deletion on chromosome 5p13. The deleted region includes exons 42-47 of the NIPBL gene. It is important to perform NIBPL mutation analysis on DNA from more than one tissue when testing for CdLS.


Assuntos
Síndrome de Lange/complicações , Região Sacrococcígea , Teratoma/complicações , Cromossomos Humanos Par 5 , Análise Mutacional de DNA , Síndrome de Lange/diagnóstico , Síndrome de Lange/genética , Evolução Fatal , Deleção de Genes , Hérnia Diafragmática/complicações , Hérnia Diafragmática/diagnóstico por imagem , Humanos , Recém-Nascido , Masculino , Proteínas/genética , Região Sacrococcígea/diagnóstico por imagem , Teratoma/diagnóstico por imagem , Ultrassonografia Pré-Natal
16.
J Med Genet ; 51(10): 659-68, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25125236

RESUMO

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS. METHODS: We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing. RESULTS: Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as 'NIPBL-like'. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases. CONCLUSIONS: Future diagnostic testing in 'mutation-negative' CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.


Assuntos
Síndrome de Lange/genética , Heterogeneidade Genética , Mosaicismo , Face/patologia , Estudos de Associação Genética , Humanos , Mutação , Fenótipo
17.
Am J Hum Genet ; 94(5): 734-44, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24726473

RESUMO

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher's exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.


Assuntos
Anormalidades Múltiplas/genética , Aracnodactilia/genética , Artrogripose/genética , Blefarofimose/genética , Fissura Palatina/genética , Pé Torto Equinovaro/genética , Doenças do Tecido Conjuntivo/genética , Contratura/genética , Deformidades Congênitas da Mão/genética , Canais Iônicos/genética , Oftalmoplegia/genética , Doenças Retinianas/genética , Anormalidades Múltiplas/patologia , Aracnodactilia/patologia , Artrogripose/patologia , Blefarofimose/patologia , Criança , Pré-Escolar , Fissura Palatina/patologia , Pé Torto Equinovaro/patologia , Doenças do Tecido Conjuntivo/patologia , Contratura/patologia , Exoma/genética , Feminino , Deformidades Congênitas da Mão/patologia , Humanos , Masculino , Mutação , Oftalmoplegia/patologia , Linhagem , Doenças Retinianas/patologia
18.
Am J Med Genet A ; 161A(12): 2972-80, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24214728

RESUMO

Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve.


Assuntos
Anormalidades Múltiplas/genética , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/genética , Transtornos do Crescimento/genética , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Complexo Repressor Polycomb 2/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Criança , Pré-Escolar , Deleção Cromossômica , Hipotireoidismo Congênito/complicações , Hipotireoidismo Congênito/fisiopatologia , Anormalidades Craniofaciais/complicações , Anormalidades Craniofaciais/fisiopatologia , Deficiências do Desenvolvimento , Proteína Potenciadora do Homólogo 2 de Zeste , Feminino , Transtornos do Crescimento/complicações , Transtornos do Crescimento/fisiopatologia , Deformidades Congênitas da Mão/complicações , Deformidades Congênitas da Mão/fisiopatologia , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/fisiopatologia , Masculino , Mutação , Fenótipo , Síndrome de Sotos/genética , Síndrome de Sotos/fisiopatologia
19.
Eur J Hum Genet ; 20(2): 240-3, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21863054

RESUMO

The imprinted expression of the IGF2 and H19 genes is controlled by the imprinting control region 1 (ICR1) located at chromosome 11p15.5. DNA methylation defects involving ICR1 result in two growth disorders with opposite phenotypes: an overgrowth disorder, the Beckwith-Wiedemann syndrome (maternal ICR1 hypermethylation in 10% of BWS cases) and a growth retardation disorder, the Silver-Russell syndrome (paternal ICR1 loss of methylation in 60% of SRS cases). In familial BWS, hypermethylation of ICR1 has been found in association with microdeletion of repetitive DNA motifs within ICR1 that bind the zinc finger protein CTCF; but more recently, ICR1 point mutations were described in BWS pedigrees. We present a case report of two brothers with BWS and prolonged post-pubertal growth resulting in very large stature. A maternally inherited point mutation was identified in ICR1 in both brothers, which altered binding of OCT transcription factors. The same mutation was present on the paternally inherited allele of their unaffected mother. This is a second report of a point mutation causing ICR1 hypermethylation by altering an OCT-binding motif. The atypical growth phenotype of the brothers may be connected to the unusual underlying cause of their BWS.


Assuntos
Síndrome de Beckwith-Wiedemann/genética , Impressão Genômica , Fator de Crescimento Insulin-Like II/genética , Mutação , Fatores de Transcrição de Octâmero/metabolismo , RNA não Traduzido/genética , Alelos , Sequência de Bases , Síndrome de Beckwith-Wiedemann/diagnóstico , Sítios de Ligação/genética , Pré-Escolar , Metilação de DNA , Ordem dos Genes , Genótipo , Humanos , Lactente , Masculino , Linhagem , Fenótipo , Regiões Promotoras Genéticas , RNA Longo não Codificante
20.
Clin Dysmorphol ; 21(1): 33-6, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22107929

RESUMO

Hall et al. (2010) describe a boy with mosaic trisomy of the proximal part of 19q, with obesity, macrocephaly and global developmental delay. The patient is interesting with regard to his cytogenetic abnormality, which is smaller than those previously reported, and does not include the candidate obesity and insulin-resistance genes identified by other authors (Zung et al., 2007; Davidsson et al., 2010) as possible causes of the overweight/obesity seen in four of five previously documented patients. This suggests that a novel obesity locus may reside in the duplicated region 19q13.11­q13.2. We present a phenotypically similar boy with intrachromosomal insertion of material derived from proximal 19q into proximal 19p, causing mosaic trisomy 19q12­q13.2, and consider the role of USF2, a master transcriptional regulator of metabolic genes, in 19q phenotypes.


Assuntos
Trissomia/genética , Fatores Estimuladores Upstream/genética , Índice de Massa Corporal , Pré-Escolar , Aberrações Cromossômicas , Cromossomos Humanos Par 19/genética , Humanos , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Megalencefalia/genética
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