In Mendelian disease genes, missense-variants may cluster in specific functional regions of the protein. Often, there is a complimentary depletion in controls due to population-level constraint. We developed two statistical methods to interrogate this signal, one for gene-association, another for variant interpretation. For gene-discovery efforts, we demonstrate how modeling clustering can improve power. For variant […]
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Prenatal clinical manifestations in individuals with COL4A1/2 variants
Heterozygous pathogenic COL4A1/2 variants cause early-onset cerebrovascular diseases, including porencephaly and schizencephaly. Although most of them are developed during prenatal periods, little had been known about their prenatal clinical features. We identified 56 individuals with pathogenic COL4A1/2 variants, and obtained prenatal clinical information in 47 individuals. Only about 30% of them exhibited prenatal findings that […]
Comprehensive characteristics of somatic mutations in the normal tissues of patients with cancer and existence of somatic mutant clones linked to cancer development
Genetic alterations including somatic mutations are the main cause of cancer and were thought therefore to be exclusively present in cancer cells. These mutations have now been identified in normal cells however, showing a significant association with increasing age. Because a cancer cell develops from a normal cell, we speculated that normal cells adjacent to […]
Otitis media susceptibility and shifts in the head and neck microbiome due to SPINK5 variants
A novel genetic variant within SPINK5 was identified in an indigenous population that has a high prevalence of otitis media (middle ear infections). Although SPINK5 was previously associated with a syndromic disease with predominant skin and hair abnormalities, the individuals who carry the novel SPINK5 variant had non-syndromic otitis media. Our findings are further supported by tissue expression and bacterial studies, and additional SPINK5 variants […]
A RIPOR2 in-frame deletion is a frequent and highly penetrant cause of adult-onset hearing loss
Hearing loss (HL) is one of the most prevalent disabilities worldwide and is highly heritable. Nevertheless, genetics of adult-onset HL is poorly understood. In this study, a DNA-variant was identified in the RIPOR2 gene as a frequent cause of HL. The HL associated with the RIPOR2-variant is highly variable and the age of onset, on […]
A novel form of rhizomelic skeletal dysplasia associated with a homozygous variant in GNPNAT1
Skeletal dysplasias are disorders which involve bone deformities and short stature. The genetic causes for some of these disorders are unknown. We describe for the first time a missense variant of a gene, GNPNAT1 which results in severe short stature in four patients due to extreme shortening of the proximal segments of the limbs. GNPNAT1 […]
Heritable genetic variants in key cancer genes link cancer risk with anthropometric traits
Physical measures, like height and weight, are known to associate with cancer risk. However, the reasons for these associations are not well understood. Here we explore if differences in our genetic code might contribute to these associations. We study the genomes of 500,000 people living in the United Kingdom and show that differences in the genetic code […]
Exome and genome sequencing in adults with undiagnosed disease: a prospective cohort study
Genetic diseases affect up to 1/50 adults, causing significant complications in many cases. Standard genetic tests often miss the diagnosis, leaving these adults without treatment options and their families without specific risk information. In our study, we used exome and genome sequencing in 47 families who were suspected to have a genetic disease, but remain undiagnosed […]
Loss of imprinting of the human-specific imprinted gene ZNF597 causes prenatal growth retardation and dysmorphic features: implications for phenotypic overlap with Silver-Russell syndrome
Various kinds of genetic and epigenetic changes can cause growth failure before and after birth. Through screening of a cohort of babies born small for gestational age, we have encountered a 6-year-old boy with prenatal growth restriction and some specific physical features. Detailed molecular analyses have revealed epigenetic alteration (epimutation) of the ZNF597 gene on […]
Sporadic vestibular schwannoma: a molecular testing summary
Our study reviews the prevalence of undiagnosed tumour predisposition disorders, schwannomatosis and NF2, in apparent cases of sporadic vestibular schwannoma (VS). We found that undiagnosed predisposition to these tumours may account for a significant proportion of apparently sporadic VS cases, especially in those presenting at a lower age. Somatic mutations in NF2 were common throughout […]