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

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.

Challenging Neuromuscular Disease Cases.

The diagnosis of neuromuscular disorders requires a thorough history including family history and examination, with the next steps broadened now beyond electromyography and neuropathology to include genetic testing. The challenge in diagnosis can often be putting all the information together. With advances in genetic testing, some diagnoses that adult patients may have received as children deserve a second look and may result in diagnoses better defined or alternative diagnoses made. Clearly defining or redefining a diagnosis can result in understanding of potential other systems involved, prognosis, or potential treatments. This article presents several cases and approach to diagnosis as well as potential treatment and prognostic concerns, including seipinopathy, congenital myasthenic syndrome, central core myopathy, and myotonic dystrophy type 2.

Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior.

PURPOSE: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis. METHODS: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes. RESULTS: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. CONCLUSION: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.

The progression of Wiedemann-Steiner syndrome in adulthood and two novel variants in the KMT2A gene.

Wiedemann-Steiner syndrome is a genetic condition associated with dysmorphic facies, hypertrichosis, short stature, developmental delay, and intellectual disability. Congenital malformations of the cerebral, cardiac, renal, and optic structures have also been reported. Because the majority of reported individuals with this condition have been under age 20, the long-term prognosis is not well defined. Here we report on two further unrelated individuals diagnosed with Wiedemann-Steiner syndrome, one of whom is in her third decade of life. In addition, both individuals have novel KMT2A mutations. The information provided below about the outcome in Wiedemann-Steiner syndrome is important for families of affected individuals.