PPP1R12A mutation leads to different genders of twinning: a case report and literature review

Loss-of-function variants in protein phosphatase 1 regulatory subunit 12A (PPP1R12A) can lead to urogenital and/or brain malformation syndrome (UBMS). When UBMS individuals exhibit genital abnormalities, it is combined with disorders of sex development (DSD). To report a PPP1R12A de novo variation in a case of 46,XY twins exhibiting different phenotypes of genital development. Twin A exhibited more feminine external genitalia (Prader III), while Twin B showed severe hypospadias (Prader IV) along with left cryptorchidism and right hernia. Endocrine evaluation and ultrasonography revealed that Twin A had bilateral gonadal dysgenesis, confirmed by gonadal pathology, while Twin B had well-functioning testes. Both twins were identical with a 46,XY karyotype. Genetic sequencing identified a novel heterozygous de novo mutation (c.1551-2A>G) in the PPP1R12A gene. Following a discussion with the multidisciplinary team (MDT) and the parents, Twin A was assigned female and underwent feminization surgery, while Twin B continued to be raised as male and received hypospadias repair. The Pre-School Activities Inventory scale was applied to assess their psychosexual development at 3.5 years old: Twin A scored 55.95 (neutral, slightly inclined to male), while Twin B scored 84.55 (male). This is the first instance of identical twins with a heterozygous mutation (c.1551-2A>G) in the PPP1R12A gene, associated with UBMS and DSD. The same variation resulted in identical twins exhibiting different genital phenotypes and choosing to live as different genders.