A new missense variant in RAB3GAP2 in a family with muscular dystrophy-short stature and defective autophagy: An expansion of the micro/Martsolf spectrum or a new phenotype?

We describe a sibling pair of Mennonite origin born from consanguineous parentage with a likely new phenotype of limb-girdle muscular dystrophy, short stature, ptosis, and tracheomalacia. Exome sequencing in the affected subjects identified a novel homozygous RAB3GAP2 missense variant as the potential causal variant. As RAB3GAP2 has been recently shown to be involved in the autophagy process, we analyzed patient-derived fibroblasts by fluorescence microscopy and demonstrated defective autophagic flux under rapamycin and serum starvation conditions when compared with wild-type cells. The phenotype in the siblings described here is distinct from Martsolf and Warburg's micro syndromes, the currently known diseases arising from RAB3GAP2 pathogenic variants. Thus, this work describes a potentially novel recessive phenotype associated with a RAB3GAP2 defect and manifesting as a muscular dystrophy-short stature disorder with no ocular anomalies. Functional analyses indicated defective autophagy in patient-derived fibroblasts, supporting the involvement of RAB3GAP2 in the etiology of this disorder. Our results contribute to a better characterization of the Martsolf/micro spectrum phenotype.

Generation of the induced pluripotent stem cell line IOCVi001-A from a patient with the MFRP-related retinitis pigmentosa-nanophthalmos syndrome.

Retinitis pigmentosa (RP) is the most common retinal degeneration in humans and is characterized by the progressive degeneration of rods and cones and retinal pigment epithelium. We generated the IOCVi001-A induced pluripotent stem cell (iPSC) line from dermal fibroblast of a patient with a homozygous c.498_499insC (p.(Asn167Glnfs⁎34) variant in the Membrane-type frizzled related protein (MFRP) gene, a genetic defect causing a syndrome characterized by RP and small eye size (nanophthalmos). IOCVi001-A displayed normal stemness, expressed pluripotent stem cell markers and displayed a normal karyotype. This iPSC line can be used for in vitro disease modeling for complex forms of RP.