Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities

Abstract

PURPOSE: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency. METHODS: Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously. We add 21 individuals with similar PRR12 variants identified via matchmaking platforms, bringing the total number to 24. RESULTS: We observed 12 frameshift, 6 nonsense, 1 splice-site, and 2 missense variants and one patient with a gross deletion involving PRR12. Three individuals had additional genetic findings, possibly confounding the phenotype. All patients had developmental impairment. Variable structural eye defects were observed in 12/24 individuals (50%) including anophthalmia, microphthalmia, colobomas, optic nerve and iris abnormalities. Additional common features included hypotonia (61%), heart defects (52%), growth failure (54%), and kidney anomalies (35%). PrediXcan analysis showed that phecodes most strongly associated with reduced predicted PRR12 expression were enriched for eye-(7/30) and kidney-(4/30) phenotypes, such as wet macular degeneration and chronic kidney disease. CONCLUSION: These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities.

Genotype–Phenotype Correlations in Relation to Newly Emerging Monogenic Forms of Autism Spectrum Disorder and Associated Neurodevelopmental Disorders: The Importance of Phenotype Reevaluation after Pangenomic Results

“…Common eye anomalies were stellate iris pattern and iris coloboma. These findings were recently confirmed by Chowdhury and colleagues [ 5 ] who described other 21 individuals with PRR12 variants including twelve frameshift, six nonsense, one splice site, two missenses, and one with a gross deletion. All patients were affected by neurodevelopmental disorders including intellectual disability (91%), speech delay (88%), and motor delay (83%).…”

Co-Essentiality Analysis Identifies PRR12 as a Regulator of Cohesin and Genome Integrity

“…Despite a non-essential role in cultured human cell lines, disruption of PRR12 function in human patients results in severe developmental and neurological impairments. Twenty-five distinct mutational variants in PRR12 have been identified across 24 patients, all of who present with developmental delays [47][48][49][50]. All of the documented variants are heterozygous mutations that occurred de novo.…”

“…All of the documented variants are heterozygous mutations that occurred de novo. Predicted loss-of-function variants in PRR12 are extremely rare according 13 to the Genome Aggregation Database (gnomAD(v3 and v2.1) suggesting that PRR12 is highly intolerant to haploinsufficiency [50]. Mutation in core cohesin regulators, including NIPBL, result in similar developmental and neurological defects, broadly defined as cohesinopathies.…”

Neurodevelopmental and other phenotypes recurrently associated with heterozygous BAZ2B loss‐of‐function variants

“…Haploinsufficiency of many human disease genes is associated with a wide phenotypic spectrum (Chowdhury et al, 2021; Muroya et al, 2001). This is likely due, at least in part, to variability in the function of the “unaffected” allele or to the effects of modifying loci whose identities are often unknown.…”