46,XY DSD with Partial Gonadal Dysgenesis and Growth Failure in a Patient with 3q27.1 Microdeletion: Candidate Gene Curation After Exhaustive Literature Review

TL;DR

A male patient with a rare genetic deletion showed symptoms of growth failure and gonadal issues, highlighting the need for genomic analysis in diagnosing complex disorders.

Contribution

The study identifies a 3q27.1 microdeletion as a potential cause of 46,XY DSD and growth failure, expanding the known phenotypic spectrum of this deletion syndrome.

Findings

A 2.7 Mb microdeletion at 3q27.1q27.2 was found in a patient with 46,XY DSD and growth failure.

Genes DVL3 and CLCN2 are suggested as possible contributors to the gonadal phenotype.

Periodic re-evaluation of sequencing data improves diagnostic yield in complex genetic cases.

Abstract

Complex genetic syndromes represent a diagnostic challenge due to their diverse phenotypic presentations, which often evolve over time and may not be fully evident at birth. Disorders of sex development (DSD) comprise congenital conditions with discordance between chromosomal, gonadal, and/or genital sex. In 46,XY gonadal dysgenesis, undervirilisation or female-appearing genitalia may occur despite a normal karyotype, and diagnosis increasingly relies on genomic approaches. Prenatal and postnatal growth failure has been described in patients with syndromic 46,XY DSD. We report a male patient with SGA, lack of postnatal catch-up growth, and syndromic dysgenetic 46,XY DSD followed longitudinally from infancy to 11 years, in whom whole-exome sequencing (WES) reanalysis revealed a pathogenic 2.7 Mb microdeletion at 3q27.1q27.2. Systematic review of previously reported 3q27.1 deletions identified overlapping phenotypes but limited documentation of gonadal dysfunction. Curation of 71 genes within the deleted region highlighted DVL3 and CLCN2 as potential contributors to the gonadal phenotype, although functional evidence remains lacking. This case expands the phenotypic spectrum of 3q27.1 microdeletion syndrome, suggesting that 46,XY gonadal dysgenesis may represent an under-recognised feature. It also underscores the importance of copy number variant (CNV) analysis and periodic re-evaluation of sequencing data to increase diagnostic yield.

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