Dataset Information

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.

SUBMITTER: Xu W

PROVIDER: S-EPMC7304352 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Hypogonadotropic hypogonadism due to variants in <i>RAB3GAP2</i>: expanding the phenotypic and genotypic spectrum of Martsolf syndrome.

Xu Wanxue W Plummer Lacey L Quinton Richard R Swords Francesca F Crowley William F WF Seminara Stephanie B SB Balasubramanian Ravikumar R

Cold Spring Harbor molecular case studies 20200612 3

Biallelic pathogenic variants in <i>RAB3GAP2</i> 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 ante ...[more]

PMID: 32376645

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Project description:BACKGROUND:Congenital hypogonadotropic hypogonadism (CHH) is a rare disease, triggered by defective GnRH secretion, that is usually diagnosed in late adolescence or early adulthood due to the lack of spontaneous pubertal development. To date more than 30 genes have been associated with CHH pathogenesis with X-linked recessive, autosomal dominant, autosomal recessive and oligogenic modes of inheritance. Defective sense of smell is present in about 50-60% of CHH patients and called Kallmann syndrome (KS), in contrast to patients with normal sense of smell referred to as normosmic CHH. ANOS1 and FGFR1 genes are all well established in the pathogenesis of CHH and have been extensively studied in many reported cohorts. Due to rarity and heterogenicity of the condition the mutational spectrum, even in classical CHH genes, have yet to be fully characterized. METHODS:To address this issue we screened for ANOS1 and FGFR1 variants in a cohort of 47 unrelated CHH subjects using targeted panel sequencing. All potentially pathogenic variants have been validated with Sanger sequencing. RESULTS:Sequencing revealed two ANOS1 and four FGFR1 mutations in six subjects, of which five are novel and one had been previously reported in CHH. Novel variants include a single base pair deletion c.313delT in exon 3 of ANOS1, three missense variants of FGFR1 predicted to result in the single amino acid substitutions c.331C?>?T (p.R111C), c.1964?T?>?C (p.L655P) and c.2167G?>?A (p.E723K) and a 15?bp deletion c.374_388delTGCCCGCAGACTCCG in exon 4 of FGFR1. Based on ACMG-AMP criteria reported variants were assigned to class 5, pathogenic or class 4, likely pathogenic. Protein structural predictions, the rarity of novel variants and amino acid conservation in case of missense substitutions all provide strong evidence that these mutations are highly likely to be deleterious. CONCLUSIONS:Despite the fact that ANOS1 and FGFR1 are classical CHH genes and were thoroughly explored in several CHH cohorts we identified new, yet undescribed variants within their sequence. Our results support the genetic complexity of the disorder. The knowledge of the full genetic spectrum of CHH is increasingly important in order to be able to deliver the best personalised medical care to our patients.

Project description:Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency (IGD) IGD is a genetically and clinically heterogeneous disorder. Mutations in many different genes are able to explain ~40% of the causes of IGD, with the rest of cases remaining genetically uncharacterized. While most mutations are inherited in X-linked, autosomal dominant, or autosomal recessive pattern, several IGD genes are shown to interact with each other in an oligogenic manner. In addition, while the genes involved in the pathogenesis of IGD act on either neurodevelopmental or neuroendocrine pathways, a subset of genes are involved in both pathways, acting as "overlap genes". Thus, some IGD genes play the role of the modifier genes or "second hits", providing an explanation for incomplete penetrance and variable expressivity associated with some IGD mutations. The clinical spectrum of IGD includes a variety of disorders including Kallmann Syndrome (KS), i.e. hypogonadotropic hypogonadism with anosmia, and its normosmic variation normosmic idiopathic hypogonadotropic hypogonadism (nIHH), which represent the most severe aspects of the disorder. Apart from these disorders, there are also "milder" and more common reproductive diseases associated with IGD, including hypothalamic amenorrhea (HA), constitutional delay of puberty (CDP) and adult-onset hypogonadotropic hypogonadism (AHH). Interestingly, neurodeveloplmental genes are associated with the KS form of IGD, due to the topographical link between the GnRH neurons and the olfactory placode. On the other hand, neuroendocrine genes are mostly linked to nIHH. However, a great deal of clinical and genetic overlap characterizes the spectrum of the IGD disorders. IGD is also characterized by a wide variety of non-reproductive features, including midline facial defects such as cleft lip and/or palate, renal agenesis, short metacarpals and other bone abnormalities, hearing loss, synkinesia, eye movement abnormalities, poor balance due to cerebellar ataxia, etc. Therefore, genetic screening should be offered in patients with IGD, as it can provide valuable information for genetic counseling and further understanding of IGD.

Dataset Information

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

Publications

Hypogonadotropic hypogonadism due to variants in <i>RAB3GAP2</i>: expanding the phenotypic and genotypic spectrum of Martsolf syndrome.

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