A number sign (#) is used with this entry because of evidence that genitourinary and/or brain malformation syndrome (GUBS) is caused by heterozygous mutation in the PPP1R12A gene (602021) on chromosome 12q21.

Genitourinary and/or brain malformation syndrome (GUBS) is characterized by variable genitourinary anomalies, including disorders of sex differentiation, and brain abnormalities ranging from agenesis of the corpus callosum to anencephaly. Other variable congenital anomalies have been observed, including omphalocele and gastrointestinal tract atresia with aberrant vessels (Hughes et al., 2020).

Hughes et al. (2020) reported 12 unrelated individuals with genitourinary and/or brain malformations and mutations in the PPP1R12A gene. Midline brain malformations were present in 5 patients, with 2 exhibiting holoprosencephaly; the most severe brain finding was anencephaly. Genitourinary anomalies were observed in 9 patients, including 4 who were 46,XY individuals with female external genitalia. Three patients showed both brain and genitourinary anomalies. Patients exhibited a wide spectrum of genitourinary phenotypes, ranging from partial gonadal dysgenesis with micropenis, hypospadias, and ambiguous genitals with Mullerian duct remnants, to complete gonadal dysgenesis in a genotypic 46,XY individual with female external genitalia. Other congenital anomalies included omphalocele, jejunal and ileal atresia with aberrant mesenteric blood supply, and syndactyly. Noting that all 9 of the 46,XY individuals had urogenital anomalies, including 3 who also exhibited brain abnormalities, whereas the 3 patients who were 46,XX only showed severe brain anomalies, the authors suggested a possible sex-influenced mechanism. However, 2 of the 46,XX patients were 'not evaluated' for genitourinary malformations; in the third 46,XX individual, genitourinary malformation was listed as 'not described on autopsy'; and 3 of the 46,XY patients were 'not evaluated' for brain malformations.

The heterozygous mutations in the PPP1R12A gene that were identified in affected members of the families with GUBS reported by Hughes et al. (2020) occurred de novo.

In 12 unrelated patients with genitourinary and/or brain malformations, Hughes et al. (2020) identified heterozygosity for de novo premature termination codon (PTC) variants in the PPP1R12A gene (see, e.g., 602021.0001-602021.0003). The authors noted that the patients exhibited a broad spectrum of clinical manifestations, and that the PPP1R12A variants occurred across multiple exons and 1 intron, with no clear genotype-phenotype correlation observed with specific variants.