Published Date: March 11, 2022

Full Text Article

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?

Authors: German A Mora-Roldan, Carlos Galaviz-Hernandez, Jose Hiebert-Froese, Arturo Hernandez, Luis Montes, Maria L Duran-Pasten, Karlen Gazarian, Juan C Zenteno

Am J Med Genet A. 2022 Jul;188(7):1972-1978. doi: 10.1002/ajmg.a.62723. Epub 2022 Mar 11.


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.

PMID: 35274444DOI: 10.1002/ajmg.a.62723