ESPE Abstracts

Our understanding of the genomic basis of Differences of Sex Development (DSD) remains incomplete, despite significant research effort and technological development in unravelling the complex network of genes that regulate gonadal development. While use of massively parallel sequencing has resulted in higher rates of identification of pathogenic or likely pathogenic variants, an accurate diagnosis is lacking for many individuals with DSD. Variants in PPP1R12A (protein phosphatase 1 regulatory subunit 12A) have previously been reported in a case series of 12 individuals with genital variation, with a new “ PPP1R12A -related urogenital +/- brain malformation syndrome” described. There was no clear genotype-phenotype correlation, however all variants reported were loss-of-function. PPP1R12A encodes a component of myosin phosphatase, a key enzyme required for regulation of cell morphology and motility. We report an additional three individuals with novel loss-of-function variants in PPP1R12A, classified as either likely pathogenic or pathogenic (ACMG classification). These variants were found through Whole Genome Sequencing with a DSD gene list applied. All families were sequenced as trios. All three individuals had gonadal dysgenesis with varying severity, with novel variants that are not reported in population or clinical databases. Patient #1 is a 46,XY female with mild virilization, indicative of partial gonadal dysgenesis, in addition to pyloric stenosis and tracheoesophageal fistula. She was found to have a pathogenic de novo frameshift variant in PPP1R12A. Patient #2 is an undervirilised 46,XY male (proximal hypospadias and bilateral undescended testes) with gonadal dysgenesis (Mullerian remnant and poor gonadal function on hCG stimulation test). He was found to have a likely pathogenic frameshift variant that was maternally inherited. Patient #3 is an undervirilised 46,XY male (micropenis and undescended testes) with gonadal dysgenesis (low AMH, Mullerian structures present). He was found to have a likely pathogenic paternally inherited frameshift variant (from an unaffected father). PPP1R12A is a recently identified gene associated with DSD and was not previously included in DSD gene panels. With the advent of whole exome and whole genome sequencing, the ability to reanalyze existing data for new genes enables the identification of new diagnoses. These patients reinforce the dominant/ de novo inheritance pattern of PPP1R12A and the potential impact of loss-of-function variants. Screening older and upcoming cohorts for variants in PPP1R12A will continue to expand our understanding of this gene and potential additional phenotypes beyond DSD and neurodevelopment.