Clinical report and genetic analysis of a neonate with genitourinary and/or brain malformation syndrome caused by a non-coding sequence variant of PPP1R12A.

BACKGROUND: Genitourinary and/or brain malformation syndrome (GUBS) is a recently discovered syndrome involving abnormalities of the neurological or urogenital system. PPP1R12A may be the pathological gene causing this syndrome. Currently, to our knowledge, there is only one study related to GUBS in the world. Here, we report a clinical case of a Chinese newborn with congenital micropenis caused by a non-coding sequence pathogenic variant of PPP1R12A, providing additional evidence on genetic causes of genital malformation.

METHODS: The genetic cause of the patient's malformation was detected using trio-whole exome sequencing and Sanger sequencing, and reverse transcription-PCR analysis was performed by constructing the minigene mutant plasmid in vitro.

RESULTS: Genetic testing revealed a novel heterozygous variant, c.2666+3A>G, of the PPP1R12A gene of the patient. The parents at this site were wild-type, indicating that this might be a de novo variant. The minigene experiment showed that the c.2666+3A>G plasmid led to the deletion of 17 bp in exon 20, and a new mRNA product c.2650_2666del (p.Thr884IleTer2) with skipping of exon 20 was produced. This may lead to PPP1R12A haploinsufficiency and cause biological harm.

CONCLUSIONS: To our knowledge, this is the first clinical study on a rare variant of PPP1R12A in the Chinese population. The c.2666+3A>G may lead to external genitalia malformation, such as congenital micropenis in male neonates. The results of this study further verified the correlation between GUBS and PPP1R12A haploinsufficiency and revealed the important role of a non-coding sequence variant in the pathogenesis of the disease.