Case Report: Novel Compound Heterozygotic Variants in PPP2R3C Gene Causing Syndromic 46, XY Gonadal Dysgenesis and Literature Review

Abstract

Purpose: Patients with syndromic 46, XY disorders/differences of sex development (DSD) are characterized by gonadal and phenotypic genders inconsistent with their chromosomal sexes as well as abnormalities of multiple extragonadal organs. They are caused by mutations in specific genes, which are expressed in the affected organs and regulate their development, and over fourteen genes have been identified. In this study, we aimed to determine the underlying cause of a patient with syndromic 46, XY DSD and review the clinical presentations and genetic findings of all reported similar cases.Methods: Whole-exome sequencing (WES) was performed to find a molecular cause of the patient. In silico tools were used to analyze the pathogenicity of the variants. Reports of cases with similar clinical features and involved genes were summarized by searching through PubMed/MEDLINE using keywords “PPP2R3C” or “G5PR” and “46,XY disorders of sex development”.Results: Compound heterozygous variants (p.F229del/p.G417E) in PPP2R3C were identified in the 24-year-old female by WES and verified by Sanger sequencing. The patient presents complete testicular dysgenesis, low birth weight, facial deformity, cubitus valgus, and decreasing number of CD19+ B lymphocytes and CD4+ T lymphocytes. A total of thirteen 46, XY DSD cases with four homozygous PPP2R3C mutations (p.Leu103Pro, p.Leu193Ser, p.Phe350Ser, and p.Ser216_Tyr218dup) have been reported previously, and their clinical manifestations are roughly similar to those of our patient.Conclusion: Novel compound heterozygous variants in PPP2R3C cause specific syndromic 46, XY gonadal dysgenesis, which broadened the pathogenic variants spectrum of PPP2R3C. The typical phenotype of PPP2R3C mutation is complete 46, XY gonadal dysgenesis with multiple extragonadal anomalies, including facial deformities, skeletal system abnormalities, muscle abnormalities, impaired nervous system, impaired hearing and vision, heart and kidney anomalies, and gastrointestinal dysfunction.

A disease-associated PPP2R3C-MAP3K1 phospho-regulatory module controls centrosome function

“…To test if syndromic mutations in PPP2R3C affect the centriolar activity of this phosphatase, we stably expressed a PPP2R3C-L193S-GFP variant in wildtype RPE1 cells, as this mutation has been observed in the largest number of MEGD individuals to date. 11 Notably, while wildtype PPP2R3C-GFP was readily detected at mother and daughter centrioles, we did not observe centriolar localization for the L193S mutant even though it was expressed in RPE1 cells at similar levels as a wildtype transgene (Fig. 4B-C).…”

“…4A). 10,11 However, the mechanistic basis by which PPP2R3C mutations cause developmental defects remains unknown. Strikingly, a similar form of gonadal dysgenesis is also reported in individuals with heterozygous variants in MAP3K1 that are proposed to be dominant gain-of-function mutations (OMIM #613762).…”

“…Following our identification of Ppp2r3c in a screen for ciliary signaling mutants, pathogenic variants in PPP2R3C were reported in patients with a developmental syndrome characterized by 46-XY complete gonadal dysgenesis, facial dysmorphism, and retinal degeneration. [9][10][11] This myoectodermal gonadal dysgenesis (MEGD) syndrome (OMIM #618419) is a recessive disorder caused by mutations at conserved PPP2R3C residues L193S, F350S, or L103P (Fig. 4A).…”

The genetic spectrum of a Chinese series of patients with 46, XY disorders of the sex development

“…Two patients with MYRF stop‐gain variants were found to have congenital strabismus or hyperopia, and one of them had streak gonads. One patient with PPP2R3C compound heterozygotic variants presented with complete gonadal dysgenesis and multiple extragonadal anomalies 7 …”