Vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP) are major causes of inherited visual impairment. Mutations in the IMPG1 gene have previously been described in patients with VMD. In the present study, we describe seven variants in IMPG1 in 11 families and provide two additional IMPG1-associated diagnoses: autosomal dominant and autosomal recessive RP. IMPG1 encodes […]
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Biallelic mutations in the TOGARAM1 gene cause a novel primary ciliopathy
Cilia are essential subcellular structures present on most cell types. Their alterations is associated with distinct disorders affecting development, particularly brain anomalies. Many genes have been associated with primary ciliopathies, but some patients lack a molecular diagnosis. Molecular analysis in a family with a malformation disorder identified mutations in TOGARAM1, which is conserved in nematodes […]
Biallelic loss-of-function ZFYVE19 mutations are associated with congenital hepatic fibrosis, sclerosing cholangiopathy and high-GGT cholestasis
Mutations in ZFYVE19, which encodes a protein involved in division of cells and in regulation of the primary cilium (an incompletely understood structure in many but not all cells), that abolish ZFYVE19 protein expression underlie a form of bile-duct and liver disease for which children may require liver transplantation. This was not known before. Manifestations of ZFYVE19 disease […]
Congenital sensorineural hearing loss as the initial presentation of PTPN11-associated Noonan syndrome with multiple lentigines or Noonan syndrome: clinical features and underlying mechanisms
Germline variants in PTPN11 are the primary cause of Noonan syndrome with multiple lentigines (NSML) and Noonan syndrome (NS), which are both autosomal dominant congenital developmental disorders with high phenotypic variability that show substantial overlap in clinical features, such as facial dysmorphism, cardiovascular defects, hearing loss, and growth retardation. The NSML/NS phenotypes are extremely heterogeneous. […]
Data-driven modelling of mutational hotspots and in silico predictors in hypertrophic cardiomyopathy
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 […]
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 […]