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.

A Nonsense ALMS1 Mutation Underlies Alström Syndrome in an Extended Mennonite Kindred Settled in North Mexico.

AIM: Alström syndrome (AS) is a rare autosomal recessive multisystem disease caused by biallelic mutations in ALMS1, a gene encoding a widely expressed centrosomal/basal body protein. Although more than 200 pathogenic mutations in ALMS1 have been identified to date in AS patients from various ethnic populations, there are very few reports of ALMS1 founder mutations in isolated populations. Our aim was to describe the molecular characterization of a cohort of AS patients from an extended inbred Mennonite kindred settled in Mexico. METHODS: Genetic study included polymerase chain reaction amplification and direct nucleotide sequencing of the entire ALMS1 gene in DNA from seven related AS patients. RESULTS: A homozygous single-nucleotide c.10480C>T substitution in exon 16, predicting a p.Q3494* nonsense mutation, was identified in all affected subjects. CONCLUSIONS: To our knowledge, this is the first demonstration of a high prevalence of AS in Mennonites, a population group maintaining high levels of consanguineous marriage in their communities. Our findings provide an example of genetic isolation and consanguinity causing a high prevalence of AS and offer the opportunity for early clinical interventions and for genetic counseling of at-risk couples in this community.