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1.
Am J Hum Genet ; 102(6): 1195-1203, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29861108

RESUMO

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.


Assuntos
Estudos de Associação Genética , Padrões de Herança/genética , Mutação com Perda de Função/genética , Transtornos do Neurodesenvolvimento/genética , Proteínas Quinases/genética , Adolescente , Adulto , Sequência de Bases , Linhagem Celular , Criança , Pré-Escolar , Fácies , Feminino , Humanos , Lactente , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Translocação Genética , Adulto Jovem
2.
J Med Genet ; 55(2): 104-113, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29097605

RESUMO

BACKGROUND: De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. OBJECTIVES: To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. METHODS: Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes. RESULTS: We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. CONCLUSION: We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.


Assuntos
Proteínas de Ligação a DNA/genética , Face/anormalidades , Deficiência Intelectual/genética , Mutação , Fatores de Transcrição/genética , Proteínas de Ligação a DNA/química , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Anormalidades do Olho/genética , Feminino , Estudos de Associação Genética , Humanos , Recém-Nascido , Hipotonia Muscular/etiologia , Hipotonia Muscular/genética , Gravidez , Homologia Estrutural de Proteína , Síndrome , Fatores de Transcrição/química
3.
Genet Med ; 19(8): 900-908, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28151491

RESUMO

PURPOSE: To characterize features associated with de novo mutations affecting SATB2 function in individuals ascertained on the basis of intellectual disability. METHODS: Twenty previously unreported individuals with 19 different SATB2 mutations (11 loss-of-function and 8 missense variants) were studied. Fibroblasts were used to measure mutant protein production. Subcellular localization and mobility of wild-type and mutant SATB2 were assessed using fluorescently tagged protein. RESULTS: Recurrent clinical features included neurodevelopmental impairment (19/19), absent/near absent speech (16/19), normal somatic growth (17/19), cleft palate (9/19), drooling (12/19), and dental anomalies (8/19). Six of eight missense variants clustered in the first CUT domain. Sibling recurrence due to gonadal mosaicism was seen in one family. A nonsense mutation in the last exon resulted in production of a truncated protein retaining all three DNA-binding domains. SATB2 nuclear mobility was mutation-dependent; p.Arg389Cys in CUT1 increased mobility and both p.Gly515Ser in CUT2 and p.Gln566Lys between CUT2 and HOX reduced mobility. The clinical features in individuals with missense variants were indistinguishable from those with loss of function. CONCLUSION: SATB2 haploinsufficiency is a common cause of syndromic intellectual disability. When mutant SATB2 protein is produced, the protein appears functionally inactive with a disrupted pattern of chromatin or matrix association.Genet Med advance online publication 02 February 2017.


Assuntos
Deficiência Intelectual/genética , Mutação com Perda de Função , Proteínas de Ligação à Região de Interação com a Matriz/genética , Mutação de Sentido Incorreto , Fatores de Transcrição/genética , Linhagem Celular , Estudos de Coortes , Estudos de Associação Genética , Haploinsuficiência/genética , Células HeLa , Humanos , Deficiência Intelectual/fisiopatologia , Proteínas de Ligação à Região de Interação com a Matriz/fisiologia , Ligação Proteica/genética , Fatores de Transcrição/fisiologia , Sequenciamento Completo do Genoma
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