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?

Abstract 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.