Edition of 27 November 2020

A new study published in the Annals of Neurology identified 11 patients in 6 families carrying 5 different biallelic pathogenic variants in specific domains of GGPS1. All but one patient presented with congenital sensorineural hearing loss, and all postpubertal females had primary ovarian insufficiency. Muscle histology was dystrophic, with ultrastructural evidence of autophagic material and large mitochondria in the most severe cases. The identification of specific GGPS1 mutations defines the cause of a unique form of muscular dystrophy with hearing loss and ovarian insufficiency.

A study published in Human Molecular Genetics identified three children from two unrelated Italian families, presenting with a previously unrecognized autosomal recessive disorder that included a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and Leber congenital amaurosis (SHILCA), as well as some brain anomalies that were visible at the MRI. Gene expression analysis revealed a 4-fold downregulation of the gene NMNAT1, residing indeed in the shared autozygous interval. Short- and long-read whole-genome sequencing highlighted a duplication involving 2 out of the 5 exons of NMNAT1 main isoform, leading to the production of aberrant mRNAs

A new study published in the American Journal of Medical Genetics reported a multiply consanguineous Syrian family where two siblings, a boy and a girl, presented with a compilation of symptoms including developmental delay, severe intellectual disability, absent speech, hearing impairment, short stature, subglottic stenosis, increased length of the palpebral fissures, onychodysplasia of index fingers, scoliosis, genu valgum, and malpositioned toes. Two other individuals from the extended family with similar clinical features are also described. Exome sequencing failed to find any causal variants.