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Review
. 2020 Jun 12;6(3):a005033.
doi: 10.1101/mcs.a005033. Print 2020 Jun.

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

Wanxue Xu  1 , Lacey Plummer  1 , Richard Quinton  2 , Francesca Swords  3 , William F Crowley  1 , Stephanie B Seminara  1 , Ravikumar Balasubramanian  1
Affiliations
Review

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

Wanxue Xu et al. Cold Spring Harb Mol Case Stud. .

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.

Keywords: hypothalamic gonadotropin-releasing hormone (GNRH) deficiency.

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Figures

Figure 1.
Figure 1.
Pedigree, multiple species alignments of RAB3GAP2 protein, electropherogram, and RAB3GAP2 variants identified to date in WARBM/MS. (A) Pedigree of index patient and segregation of RAB3GAP2 variants identified in this report; (B) multispecies protein conservation of novel missense variant (p.Arg428Glu) found in index individual showing conservation from humans to zebrafish; (C) electropherograms of variants identified in this study; and (D) schematic of RAB3GAP2 protein showing MS-associated RAB3GAP2 variants identified in this report (shown above protein schematic; in green and blue) and RAB3GAP2 variants reported in the literature (shown below protein schematic). (Red) WARBM-associated variants, (black) MS-associated variants. The RAB3GAP2 protein domains were defined using Interpro (Mitchell et al. 2019) and Pfam (El-Gebali et al. 2019) resources.
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