Genitourinary and/or Brain Malformation Syndrome (GUBS) via the PPP1R12A Gene

Genitourinary and/or brain malformation syndrome (GUBS) is a congenital disorder primarily characterized by genitourinary anomalies and/or brain abnormalities. Major characteristics include developmental delay, brain malformations, and genitourinary (GU) malformations. Reported brain malformations include holoprosencephaly, corpus callosum abnormalities, anencephaly, absent septum pellucidum, and neuronal migrations defects such as polymicrogyria and heterotopia. The reported GU malformations include micropenis, chordee, hypospadias, cryptorchidism, and persistent Müllerian duct. Minor features can include dysmorphic facial features, omphalocele, and eye anomalies such as strabismus, esotropia, visual impairment, nystagmus, astigmatism and hyperopia (Hughes et al. 2020. PubMed ID: 31883643).

As this is a recently described disorder that shares phenotypic overlap with a number of other congenital disorders, it is difficult to estimate the incidence of GUBS; however, it is expected to be rare.

Advantages of testing for variants in PPP1R12A include molecular confirmation of a clinical diagnosis and identification of de novo variants in known or suspected cases. In general, larger panel testing is recommended for identifying an unknown genetic cause in developmental delay and brain malformation cases.

GUBS is caused by heterozygous variants in the PPP1R12A gene. All disease causing variants reported thus far have been de novo loss of function (LOF) variants, including nonsense, frameshift, and splice acceptor loss (Hughes et al. 2020. PubMed ID: 31883643). To date, copy number variant alterations of PPP1R12A have not been associated with GUBS.

In gnomAD, PPP1R12A is predicted to tolerate missense variants, but has very low tolerance for LOF variants. The most common LOF variant in gnomAD is c.1823+2T>C, which has a minor allele frequency of 0.009%. The pathogenic variants reported by Hughes and colleagues (Hughes et al. 2020. PubMed ID: 31883643) are not present in gnomAD.

Several animal models including mouse, C. elegans, and Drosophila have been generated that demonstrate a role for the homologues of PPP1R12A in embryonic development (Okamoto et al. 2005. PubMed ID: 16145842; Wissmann et al. 1999. PubMed ID: 10208747; Mizuno et al. 2002. PubMed ID: 11874917; Tan et al. 2003. PubMed ID: 12505998). Of note, a zebrafish model was shown to have malformations consistent with phenotypes observed in humans with holoprosencephaly (Weiser et al. 2009. PubMed ID: 19515695). PPP1R12A has been cited as an essential gene under certain conditions--meaning that some cell lines require PPP1R12A for proliferation, whereas others do not (Online Gene Essentiality, ogee.medgenius.info).

PPP1R12A encodes a subunit of the myosin phosphatase protein which is a key enzyme for regulating cell motility and morphology (Kiss et al. 2019. PubMed ID: 30076859). For example, the subunit encoded by PPP1R12A is essential for smooth muscle contraction (Qiao et al. 2014. PubMed ID: 24951589).

The clinical sensitivity of this test is difficult to estimate based on the phenotypic overlap with other disorders featuring developmental delay, brain malformations, and/or genitourinary malformations. Other disorders with similar clinical features include Smith-Lemli-Opitz syndrome, X-linked lissencephaly, orofacial digital syndrome IV, pontocerebellar hypoplasia type 7, and other conditions featuring brain and genitourinary anomalies. Analytical sensitivity should be high.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the PPP1R12A gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or 2x Sanger sequencing.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).