Dataset Information

Prevalence and Phenotypic Effects of Copy Number Variants in Isolated Hypogonadotropic Hypogonadism.

ABSTRACT:

Context

The genetic architecture of isolated hypogonadotropic hypogonadism (IHH) has not been completely defined.

Objective

To determine the role of copy number variants (CNVs) in IHH pathogenicity and define their phenotypic spectrum.

Methods

Exome sequencing (ES) data in IHH probands (n = 1394) (Kallmann syndrome [IHH with anosmia; KS], n = 706; normosmic IHH [nIHH], n = 688) and family members (n = 1092) at the Reproductive Endocrine Unit and the Center for Genomic Medicine of Massachusetts General Hospital were analyzed for CNVs and single nucleotide variants (SNVs)/indels in 62 known IHH genes. IHH subjects without SNVs/indels in known genes were considered "unsolved." Phenotypes associated with CNVs were evaluated through review of patient medical records. A total of 29 CNVs in 13 genes were detected (overall IHH cohort prevalence: ~2%). Almost all (28/29) CNVs occurred in unsolved IHH cases. While some genes (eg, ANOS1 and FGFR1) frequently harbor both CNVs and SNVs/indels, the mutational spectrum of others (eg, CHD7) was restricted to SNVs/indels. Syndromic phenotypes were seen in 83% and 63% of IHH subjects with multigenic and single gene CNVs, respectively.

Conclusion

CNVs in known genes contribute to ~2% of IHH pathogenesis. Predictably, multigenic contiguous CNVs resulted in syndromic phenotypes. Syndromic phenotypes resulting from single gene CNVs validate pleiotropy of some IHH genes. Genome sequencing approaches are now needed to identify novel genes and/or other elusive variants (eg, noncoding/complex structural variants) that may explain the remaining missing etiology of IHH.

SUBMITTER: Stamou MI

PROVIDER: S-EPMC9282252 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Prevalence and Phenotypic Effects of Copy Number Variants in Isolated Hypogonadotropic Hypogonadism.

Stamou Maria I MI Brand Harrison H Wang Mei M Wong Isaac I Lippincott Margaret F MF Plummer Lacey L Crowley William F WF Talkowski Michael M Seminara Stephanie S Balasubramanian Ravikumar R

The Journal of clinical endocrinology and metabolism 20220701 8

<h4>Context</h4>The genetic architecture of isolated hypogonadotropic hypogonadism (IHH) has not been completely defined.<h4>Objective</h4>To determine the role of copy number variants (CNVs) in IHH pathogenicity and define their phenotypic spectrum.<h4>Methods</h4>Exome sequencing (ES) data in IHH probands (n = 1394) (Kallmann syndrome [IHH with anosmia; KS], n = 706; normosmic IHH [nIHH], n = 688) and family members (n = 1092) at the Reproductive Endocrine Unit and the Center for Genomic Medic ...[more]

PMID: 35574646

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Project description: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.

Dataset Information

Prevalence and Phenotypic Effects of Copy Number Variants in Isolated Hypogonadotropic Hypogonadism.

Context

Objective

Methods

Conclusion

Publications

Prevalence and Phenotypic Effects of Copy Number Variants in Isolated Hypogonadotropic Hypogonadism.

Similar Datasets

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