Translocations Disrupting PHF21A in the Potocki-Shaffer-Syndrome Region Are Associated with Intellectual Disability and Craniofacial Anomalies

Abstract

Potocki-Shaffer syndrome (PSS) is a contiguous gene disorder due to the interstitial deletion of band p11.2 of chromosome 11 and is characterized by multiple exostoses, parietal foramina, intellectual disability (ID), and craniofacial anomalies (CFAs). Despite the identification of individual genes responsible for multiple exostoses and parietal foramina in PSS, the identity of the gene(s) associated with the ID and CFA phenotypes has remained elusive. Through characterization of independent subjects with balanced translocations and supportive comparative deletion mapping of PSS subjects, we have uncovered evidence that the ID and CFA phenotypes are both caused by haploinsufficiency of a single gene, PHF21A, at 11p11.2. PHF21A encodes a plant homeodomain finger protein whose murine and zebrafish orthologs are both expressed in a manner consistent with a function in neurofacial and craniofacial development, and suppression of the latter led to both craniofacial abnormalities and neuronal apoptosis. Along with lysine-specific demethylase 1 (LSD1), PHF21A, also known as BHC80, is a component of the BRAF-histone deacetylase complex that represses target-gene transcription. In lymphoblastoid cell lines from two translocation subjects in whom PHF21A was directly disrupted by the respective breakpoints, we observed derepression of the neuronal gene SCN3A and reduced LSD1 occupancy at the SCN3A promoter, supporting a direct functional consequence of PHF21A haploinsufficiency on transcriptional regulation. Our finding that disruption of PHF21A by translocations in the PSS region is associated with ID adds to the growing list of ID-associated genes that emphasize the critical role of transcriptional regulation and chromatin remodeling in normal brain development and cognitive function.

Old gene, new phenotype: mutations in heparan sulfate synthesis enzyme, EXT2 leads to seizure and developmental disorder, no exostoses

“…Interestingly, there has only been one report of HME and seizures in a patient with a mutation in EXT2 29. There have been multiple reports of patients with multiple exostoses, intellectual disability and seizures, diagnosed with Potocki–Shaffer syndrome (OMIM 601224), a rare contiguous gene deletion syndrome due to haploinsufficiency of the 11p11.2 region, encompassing EXT2 30 31. In addition, partial loss of EXT2 sister protein, EXT1 and TRPS1, its neighbouring gene, can give rise to another developmental disorder known as Langer–Giedion syndrome (OMIM 150230), which is characterised by multiple cartilaginous exostoses, dysmorphic facial appearance and mild intellectual disability 32 33.…”

A de novo t(10;19)(q22.3;q13.33) leads to ZMIZ1/PRR12 reciprocal fusion transcripts in a girl with intellectual disability and neuropsychiatric alterations

“…Moreover, through either balanced translocation characterization or next generation sequencing approaches, mutations in a set of evolutionarily conserved autosomal genes that encode SWI/ SNF complex factors that participate in chromatin remodeling to facilitate gene expression needed in neuronal development and other cellular processes have been identified. Thus, mutations in ARID1A, ARID1B, SMARCA2, SMARCA4, SMARCB1, and SMARCE1 genes belonging to that complex, or PHF21A, outside the complex, have been related to some congenital ID disorders [8,11,12]. In this report, we thoroughly characterized a de novo t (10;19) balanced translocation that led to disruption and subsequent fusion of the chromatin remodeling-related zinc finger, MIZ-type containing 1 (ZMIZ1) and proline-rich 12 (PRR12) genes in a girl with ID and multiple neuropsychiatric alterations.…”

Disrupted Intricacy of Histone H3K4 Methylation in Neurodevelopmental Disorders

“…It may only be a matter of time before alterations in the remaining four enzymes are identified in neurological disorders. Furthermore, genetic mutations in two reader proteins for H3K4me status, PHF21A and PHF8, have been associated with ID syndromes [20,21] (Figure 1). Here, we aim to summarize the recent progress in understanding the molecular and cellular consequences of mutations in H3K4me regulators.…”