Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations

Abstract

In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and individuals with disorders of sex development, and through international research collaboration, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved in cell migration, adhesion, and morphogenesis. This gene has not been previously reported in association with human disease, and it has intolerance to LoF as illustrated by a very low observed-to-expected ratio of LoF variants in gnomAD. Of the twelve individuals, midline brain malformations were found in five, urogenital anomalies in nine, and a combination of both phenotypes in two. Other congenital anomalies identified included omphalocele, jejunal, and ileal atresia with aberrant mesenteric blood supply, and syndactyly. Six individuals had stop gain variants, five had a deletion or duplication resulting in a frameshift, and one had a canonical splice acceptor site loss. Murine and human in situ hybridization and immunostaining revealed PPP1R12A expression in the prosencephalic neural folds and protein localization in the lower urinary tract at critical periods for forebrain division and urogenital development. Based on these clinical and molecular findings, we propose the association of PPP1R12A pathogenic variants with a congenital malformations syndrome affecting the embryogenesis of the brain and genitourinary systems and including disorders of sex development.

Identifying environmental risk factors and gene–environment interactions in holoprosencephaly

“…Like many other birth defects (Zhu, Kartiko, & Finnell, 2009), the etiology of HPE is heterogeneous with complex interactions between genetic aberrations and nongenetic exposures (Addissie et al, 2020; Bendavid et al, 2010; Grinblat & Lipinski, 2019; Hong & Krauss, 2018; Krauss & Hong, 2016). The genetic etiology of HPE includes structural chromosomal anomalies (Kruszka, Martinez, & Muenke, 2018; Solomon, Gropman, & Muenke, 2013), monogenic syndromes in which HPE is a feature (Kruszka & Muenke, 2018), and isolated (nonsyndromic, nonchromosomal) cases in which HPE is the only finding (Hughes et al, 2020; Kruszka, Berger, Casa, et al, 2019; Kruszka, Berger, Weiss, Everson, Martinez, Hong, Anyane‐Yeboa, et al, 2019; Kruszka, Martinez, & Muenke, 2018). The four genes most commonly found in isolated HPE are SHH , ZIC2 , SIX3 , and FGFR1 , with pathogenic variants in more than 12 additional genes found in much lower frequency, and additional genes being discovered with the application of next‐generation sequencing (Dubourg et al, 2016; Hughes et al, 2019; Kruszka et al, 2019; Kruszka et al, 2019b; Kruszka, Martinez, & Muenke, 2018; Roessler, Hu, & Muenke, 2018).…”

Shared Neurodevelopmental Perturbations Can Lead to Intellectual Disability in Individuals with Distinct Rare Chromosome Duplications

“…For instance, PTK2 (chr:8) interacts directly with OCRL (inositol polyphosphate-5-phosphatase—chr:X), DCX (doublecortin—chr:X) with LAMA1 (laminin subunit α 1—chr:18), or yet, KCNQ3 (potassium voltage-gated channel subfamily Q member 3—chr:8) and LAMA1 are connected to each other by the neurotrophic tyrosine receptor kinase ( NTRK3 ) ( Figure 5 a). Furthermore, OCRL and PTK2 interacts directly with WAC , QKI , and PPP1R12A , genes previously associated with ID [ 69 , 70 , 71 , 72 ]. In the case of PPP1R12A , its loss-of-function causes holoprosencephaly and ID in individuals with stop gain variants and deletions/duplications, resulting in a frameshift effect [ 72 ].…”

Transposable element-derived sequences in vertebrate development

“…Another antisense SINEUP lncRNA, isolated from human brain, contains a free right Alu monomer element and increases the translation of the gene expressing the phosphatase 1 regulatory subunit 12A (PPP1R12A) [ 206 ]. PPP1R12A presents human pathogenic variants that have been associated with a congenital malformation syndrome affecting brain embryogenesis [ 207 ] and is involved in the development of the central nervous system in zebrafish [ 208 ]. More than 100 potential additional antisense SINEUP lncRNAs expressed in human brain have been identified [ 206 ], revealing other candidates for SINEUP-regulated genes involved in brain development and functioning.…”