PHF21A Related Disorder: Description of a New Case

Abstract

PHF21A (PHD finger protein 21A) gene, located in the short arm of chromosome 11, encodes for BHC80, a component of the Lysine Specific Demethylase 1, Corepressor of REST (LSD1-CoREST) complex. BHC80 is mainly expressed in the human fetal brain and skeletal muscle and acts as a modulator of several neuronal genes during embryogenesis. Data from literature relates PHF21A variants with Potocki–Shaffer Syndrome (PSS), a contiguous gene deletion disorder caused by the haploinsufficiency of PHF21A, ALX4, and EXT2 genes. Clinical cardinal features of PSS syndrome are multiple exostoses (due to the EXT2 involvement), biparietal foramina (due to the ALX4 involvement), intellectual disability, and craniofacial anomalies (due to the PHF21A involvement). To date, to the best of our knowledge, a detailed description of PHF21A-related disorder clinical phenotype is not described in the literature; in fact, only 14 subjects with microdeletion frameshift or nonsense variants concerning only PHF21A gene have been reported. All reported cases did not present ALX4 or EXT2 variants, and their clinical features did not fit with PSS diagnosis. Herein, by using Exome sequencing, and Sanger sequencing of the region of interest, we describe a case of a child with a paternally inherited (mosaicism of 5%) truncating variant of the PHF21A gene (c.649_650del; p.Gln217ValfsTer6), and discuss the new evidence. In conclusion, these patients showed varied clinical expressions, mainly including the presence of intellectual disability, epilepsy, hypotonia, and dysmorphic features. Our study contributes to describing the genotype–phenotype spectrum of patients with PHF21A-related disorder; however, the limited data in the literature have been unable to provide a precise diagnostic protocol for patients with PHF21A-related disorder.

A novel de novo variant in the PHF21A causes craniofacial abnormalities, intellectual disability and skeletal manifestations

“…Herein, we genetically and clinically characterized a proband having moderate–severe ID, global developmental delay, ID, tonic seizures, ADHD, mild‐microcephaly, and speech issues. Features reported in our patient overlapped with the features reported previously 1,3–5 . However, unlike macrocephaly reported in the previous cases our patient revealed mild microcephaly 1 …”

“…The Zebrafish indicated that PHF21A dosage are essential for craniofacial and neurodevelopment, while PHF21A suppression leads to abnormal head, face, jaw, and increased neuronal apoptosis. Importantly, these deficiencies were rescued by the human PHF21A , indicating a conserved developmental function 1,4,5 …”

“…PHF21A transcripts were ten‐fold higher in the cerebellum, nine‐fold higher in the occipital lobe, and five‐fold more elevated in the hippocampus, associated with learning and memory. PHF21A encodes a protein that binds un‐methylated H3K4 explicitly as part of a histone demethylase complex that participates in the suppression of neuronal gene expression 1,3–5 . The Zebrafish indicated that PHF21A dosage are essential for craniofacial and neurodevelopment, while PHF21A suppression leads to abnormal head, face, jaw, and increased neuronal apoptosis.…”

Coexistent ankylosing spondylitis and intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures

“…4 Although the phenotypic spectrum of intellectual disabilities, developmental delays, facial anomalies, overgrowth, and obesity in our case was generally consistent with that of previously reported cases, the pathogenic variant carried by our patient differed from those in previous reports. 4,5,12,13 This finding reinforces that PHF21A haploinsufficiency could contribute to intellectual developmental disorders and facial dysmorphism. Compared with previous cases, our patient showed no obvious cranial anomalies, finger anomalies, epilepsy, hypotonia, or diagnosis of ASD or attention-deficit hyperactivity disorder.…”

“…7 To date, 15 cases have been reported involving microdeletion frameshift or nonsense variants in the PHF21A gene. 4,5,[8][9][10][11][12][13] This report describes AS coexisting with a PHF21A-related disorder.…”