During the early stages of embryo growth, the SRY gene located on the Y chromosome triggers male sexual development. Typically, embryos with two X chromosomes develop into females. We report a child with two X chromosomes who had male appearing genitalia (female-to-male sex reversal) due to a deletion of a small X chromosome segment controlling […]
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Missense mutations in the WD40 domain of AHI1 cause non-syndromic retinitis pigmentosa
Pathogenic variants (mutations) in the Abelson helper integration site 1 (AHI1) gene are known to be associated with Joubert syndrome, a developmental disorder causing visual, cognitive and motor deficits. In this study, we show that some pathogenic variants in the AHI1 gene can cause visual impairment, without other symptoms or signs suggestive of Joubert syndrome. […]
Confirmation of mutations in PROSC as a novel cause of vitamin B6-dependent epilepsy
Early onset epilepsy with resistance to common anticonvulsants can be due to genetic defects that respond to high doses of vitamin B6. We describe four patients with neonatal, pyridoxine (vitamin B6) responsive seizures and disease causing variants in the PROSC gene, which regulates vitamin B6 metabolism in body cells. Three patients had favorable outcome with […]
Somatic mosaicism containing double mutations in PTCH1 revealed by generation of induced pluripotent stem cells from nevoid basal cell carcinoma syndrome
As next generation sequencers are widely used, somatic mosaicism is thought to be more common than previously expected. We report a mosaic patient with nevoid basal cell carcinoma syndrome, a genetic condition featured by minor anomalies and high prevalence of cancers such as basal cell carcinoma and medulloblastoma. The patient had a germline PTCH1 mutation, […]
Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus
One of the major susceptibility loci identified for Systemic lupus erythematosus (SLE) lies within a common large inversion polymorphism region on chromosome 8p23. In this study, we further investigated the ‘extended’ 8p23 locus (~4 Mb) where we observed multiple SLE signals and assessed these signals for their relation to the inversion affecting this region. The […]
15 years of research on Oral-Facial-Digital syndromes: from 1 to 16 causal genes
Oral-facial-digital syndromes (OFDS) are rare genetic disorders characterized by the association of abnormalities of the face, oral cavity and extremities. Molecular bases were poorly known but we suspected the involvement of ciliary genes. Using whole-exome sequencing in 24 OFDS cases, we identified causal variants in five new genes, two genes previously implicated in OFDS and […]
Novel and known ribosomal causes of Diamond-Blackfan anemia identified through comprehensive genomic characterization
Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome primarily caused by defects in ribosome biology. It is associated with physical anomalies and high risk of specific cancers. We performed comprehensive genomic analyses of 35 genetically uncharacterized DBA families participating in the National Cancer’s Institute’s DBA cohort (ClinicalTrials.gov Identifier: NCT00027274). Using whole exome sequencing, […]
A truncating mutation in CEP55 is the likely cause of MARCH, a novel syndrome affecting neuronal mitosis
Hydranencephaly, a congenital anomaly caused by destruction of the cerebral hemispheres is usually found in isolation. We report a family in which three fetuses displayed multinucleated neurons, anhydramnios, renal dysplasia, and cerebellar hypoplasia together with hydranencephaly, a novel syndrome we have named MARCH. Sequencing revealed the cause to be a homozygous truncating mutation in CEP55, […]
Bi-allelic variants in COL3A1 encoding the ligand to GPR56 are associated with cobblestone-like cortical malformation, white matter changes and cerebellar cysts
Collagens are important constituents of connective tissue but are also present in the membrane lining the surface of the brain. The COL3A1 gene encodes the chains of type III procollagen. Mutation of one copy of this gene results in vascular Ehlers Danlos syndrome (EDS), a connective tissue disorder. We now have discovered that mutations of […]
A missense mutation in the CRBN gene that segregates with intellectual disability and self-mutilating behaviour in a consanguineous Saudi Family
Here, we report five members affected with severe intellectual disability, developmental delays, seizures, and self-mutilation in a large consanguineous family from Saudi Arabia. Clinical whole-exome sequencing in the proband revealed a pathogenic variant in the CRBN gene, which segregated in the family. CRBN protein is known to play a role in memory and learning by […]