Hypogonadotropic hypogonadism due to variants in RAB3GAP2: expanding the phenotypic and genotypic spectrum of Martsolf syndrome

Abstract

Biallelic pathogenic variants in RAB3GAP2 cause Warburg Micro syndrome (WARBM) and Martsolf syndrome (MS), two rare, phenotypically overlapping disorders characterized by congenital cataracts, intellectual disability, and hypogonadism. Although the initial report documented hypergonadotropic hypogonadism (implying a gonadal defect), an adolescent girl with WARBM/MS was subsequently reported to have hypogonadotropic hypogonadism (implying a central defect in either the hypothalamus or anterior pituitary). However, in adult MS, hypogonadotropism has not been convincingly demonstrated. Additionally, the correlation between the pathogenic severity of variants in RAB3GAP2 and the phenotypic severity also remains unclear. Here we present a clinical report of a woman with congenital cataracts, apparent intellectual disability, and pubertal failure who underwent exome sequencing (ES) to determine a precise molecular diagnosis. Reproductive phenotypes reported previously in individuals with MS and the genotypic spectrum of previous RAB3GAP2 variants were also reviewed. The ES identified pathogenic compound heterozygous RAB3GAP2 variants (c.387-2A > G; p.(Arg428Glu)) combined with her phenotypic features, which enabled a unifying molecular diagnosis of MS. Reproductive evaluation confirmed a normosmic idiopathic hypogonadotropic hypogonadism. Review of the RAB3GAP2 allelic spectrum in WARBM/MS suggests that although variants resulting in complete abrogation of RAB3GAP2 protein function cause severe WARBM, variants associated with partially preserved RAB3GAP2 function cause milder MS. This report expands the genotypic and phenotypic spectrum of MS and demonstrates hypogonadotropic hypogonadism as a key pathophysiologic abnormality in MS. Genotype-phenotype associations of previously reported RAB3GAP2 variants indicate that variants that fully abolish RAB3GAP2 function result in WARBM, whereas MS is associated with variants of lesser severity with residual RAB3GAP2 function.

Phenotype and genotype spectrum of variants in guanine nucleotide exchange factor genes in a broad cohort of Iranian patients

“…The frequency of different ID types in these patients was as follow; 89.7% and 8.1% of patients with RAB3GAP1 variants had severe to profound and moderate ID, respectively while 43.3%, 23.3%, and 16.6% of cases with RAB3GAP2 variants showed severe to profound, moderate, and mild ID, respectively (Table S2). It is noteworthy that cases with WARBM1 syndrome mostly showed severe to profound ID while patients with Martsolf syndrome manifested variable phenotype mostly from mild to moderate ID, especially in cases with mutations in RAB3GAP2 (Abdel‐Hamid et al, 2020; Aligianis et al, 2005; Handley et al, 2013; Xu et al, 2020).…”

Micro and Martsolf syndromes in 34 new patients: Refining the phenotypic spectrum and further molecular insights

“…However, the involvement of epigenetic or environmental factors cannot be ruled out. In view of all molecularly defined families with Martsolf, four had mutations in RAB3GAP2 , 3,6,12 two had mutations in RAB3GAP1 , 3,13 and one family had a mutation in TBC1D20 14 . In addition, Gumus reported a family with overlapping features of the two syndromes due to a splice site mutation in RAB3GAP2 gene 11 …”

“…Till now, around 100 families from diverse ethnic groups were molecularly confirmed as Micro syndrome where mutations in RAB3GAP1 were the most common cause (frequency 75%) 3,9,10 . As for Martsolf syndrome, RAB3GAP2 mutations have been described in five families, 3,6,11,12 while RAB3GAP1 and TBC1D20 mutations were found in two and one families, respectively 3,13,14 …”

“…mutations have been described in five families, 3,6,11,12 while RAB3GAP1 and TBC1D20 mutations were found in two and one families, respectively. 3,13,14 In this report, we describe the detailed clinical, neuro-radiological and genetic findings of a large cohort of patients with Micro and Martsolf syndromes.…”

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?

“…While muscular dystrophy has not been reported in Martsolf/micro syndromes, cardiomyopathy has been identified in affected subjects (Kabzi nska et al, 2016). Recently, the Martsolf/ micro syndrome phenotypes have been expanded by the recognition of hypogonadotropic hypogonadism (Xu et al, 2020) and pectus excavatum/carinatum and congenital heart disease (Abdel-Hamid et al, 2020), indicating that the phenotypic spectrum in these disorder syndromes is broader than previously assumed. Unfortunately, brain MRIs were not available in our patients, precluding the identification of potential CNS malformations.…”