RESUMO
Cohen syndrome is caused by homozygous mutation in the vacuolar protein sorting 13 homolog B (VPS13B, also referred to as COH1) gene on chromosome 8q22.2. The VPS13B protein is involved in transmembrane transport, Golgi integrity, and neuritogenesis. Clinical manifestations of Cohen syndrome are mainly intellectual disability, developmental delay, facial abnormalities, and eye disorders. This study aimed to identify the causative variant in two unrelated families with Cohen syndrome. To this end, whole-exome sequencing (WES) was performed to identify the pathogenic variants. A homozygous nonsense variant (NM_017890:c.10369C > T; NP_060360.3: p.Q3457X) in the VPS13B gene was identified and co-segregated with all affected individuals in both families. In silico analysis highly suggested this variant as damaging for protein function. The present study increases the mutation spectrum of the VPS13B gene and could be useful in genetic diagnosis and genetic counseling in Cohen syndrome patients.
Assuntos
Dedos/anormalidades , Deficiência Intelectual/genética , Microcefalia/genética , Hipotonia Muscular/genética , Miopia/genética , Obesidade/genética , Degeneração Retiniana/genética , Proteínas de Transporte Vesicular/genética , Criança , Códon sem Sentido , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Dedos/patologia , Homozigoto , Humanos , Deficiência Intelectual/patologia , Masculino , Microcefalia/patologia , Hipotonia Muscular/patologia , Miopia/patologia , Obesidade/patologia , Fenótipo , Degeneração Retiniana/patologia , Sequenciamento do Exoma , Adulto JovemRESUMO
Background: Hearing loss (HL) is one of the most common and genetically heterogeneous sensory disorders in humans. Genetic causes underlie 50-60% of all HL and the majority of these cases exhibit an autosomal recessive model of inheritance. Methods: In our study, we used our targeted custom MiamiOtoGenes panel of 180 HL-associated genes to screen 23 unrelated consanguineous Iranian families with at least two affected children to identify potential causal variants for HL. Results: We identified pathogenic variants in seven genes (MYO7A, CDH23, GIPC3, USH1C, CAPB2, LOXHD1, and STRC) in nine unrelated families with varying HL profiles. These include five reported and four novel mutations. Conclusion: For small consanguineous families that were unsuitable for conventional linkage analysis the employment of the MiamiOtoGenes panel helped identify the genetic cause of HL in a cost-effective and timely manner. This rapid methodology provides for diagnoses of a significant fraction of HL patients, and identifies those who will need more extensive genetic analyses such as whole exome/genome sequencing.
Assuntos
Testes Genéticos/métodos , Perda Auditiva/diagnóstico , Adulto , Criança , Pré-Escolar , Surdez/genética , Exoma/genética , Família , Feminino , Ligação Genética/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Mutação/genética , Mutação de Sentido Incorreto/genética , Linhagem , Sequenciamento do Exoma/métodosRESUMO
Hearing loss (HL) is a common sensory disorder in humans with high genetic heterogeneity. To date, over 145 loci have been identified to cause nonsyndromic deafness. Furthermore, there are countless families unsuitable for the conventional linkage analysis. In the present study, we used a custom capture panel (MiamiOtoGenes) to target sequence 180 deafness-associated genes in 5 GJB2 negative deaf probands with autosomal recessive nonsyndromic HL from Iran. In these 5 families, we detected one reported and six novel mutations in 5 different deafness autosomal recessive (DFNB) genes (TRIOBP, LHFPL5, CDH23, PCDH15, and MYO7A). The custom capture panel in our study provided an efficient and comprehensive diagnosis for known deafness genes in small families.
Assuntos
Ligação Genética/genética , Perda Auditiva/genética , Feminino , Heterogeneidade Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Irã (Geográfico) , Masculino , Mutação/genética , LinhagemRESUMO
BACKGROUND: Joubert syndrome (JS) is a clinically and genetically heterogeneous group of rare neurodevelopmental disorder characterised by peculiar midbrain-hindbrain malformation, known as the "molar tooth" sign. JS can manifest a broad range of signs and symptoms. The most common features of JS are hypotonia, ataxia, developmental delay/intellectual disability, abnormal eye movements, and neonatal breathing abnormalities. To date, 29 genes have been shown to cause JS. METHODS: We employed whole-genome single nucleotide polymorphism genotyping in a group of Iranian families with JS and Sanger sequencing of a known mutation associated with JS located in a single homozygous regions shared by affected members of the families. RESULTS: Homozygosity mapping uncovered a shared â¼2.2-Mb run of homozygosity on chromosome 8q21.3-q22.1 encompassing the known JS-causing TMEM67 gene. Sanger sequencing of a known mutation (NM_153704.5: c.725A>G; p.Asn242Ser) in TMEM67 identified from studying another Iranian family using whole-exome sequencing confirmed the presence of the homozygous mutation in 22 affected members of 12 nuclear families. "Molar tooth" sign of brain magnetic resonance imaging, moderate-to-severe neurodevelopmental delay, and abnormal eye movements were the most common features of affected individuals. In addition, liver disease, seizure, behavioural abnormalities, failure to thrive, and kidney disease were observed variably in some of the patients. CONCLUSION: We propose that Asn242Ser is a founder mutation in the Iranian population, which might explain a significant proportion of JS cases from eastern Iran. Therefore, screening for this variant should be considered for genetic testing in Iranian patients with JS. In addition, this finding is important for developing population-specific genetic testing in Iran.
