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.

Keywords: BHC80; PHF21A gene; Potocki–Shaffer syndrome; contiguous gene deletion; human chromosome 11; hypotonia; intellectual disability.

Figure 1

Pictures of the patient presenting a truncating variant (c.649_650del; p.Gln217ValfsTer6) of the PHF21A gene. Left: front picture showing round face and reduced head circumference. Right: profile picture showing moderate micrognathia and low-set, anteriorly rotated ears.

Figure 2

Visualization of the frameshift mutation in PHF21A gene: (a–c) from top to bottom (i) the NGS data with Integrative Genomics Viewer, (ii) the nucleotide sequence with the direction of the reading frame, (iii) the wild-type and the mutated aminocid sequences, and (iv) the electropherogram obtained by Sanger sequencing. The two-bases deletion c.649_650del (p.Gln217ValfsTer6) determining the frameshift mutation in PHF21A gene (NM_001101802) is represented in the colored lines of the NGS viewer with or without deletion (some reads are shown as examples). In the mutated protein, the divergent aminoacids were indicated in red. The heterozygous patient shows 50% reads with the causative deletion, whereas the father presents the heterozygous mutation in ~5% of his blood cells (7 of 146 reads), and the mother only the homozygous normal PHF21A allele. It is evident in the Sanger sequences the difference among patient, father, and mother with the deletion determining the phase displacement of the two allele sequences highlighted in the right part of the electropherograms in the patient and in the father. (d) Aminocid sequence of the PHF21A protein in the wild-type condition, and in the mutated form following the two-bases deletion; five aminoacids were translated, and then the protein was truncated due to the presence of a STOP codon (p.Gln217ValfsTer6). The aminoacid sequence shown in the upper panels is highlighted in pale blue.

Figure 3

PHF21A gene organization, and major described mutations. Human PHF21A gene is located in chromosome 11 (band p.11.2). The gene, composed by 18 exons, is transcribed from its centromeric to telomeric side (upper part of the figure). At the bottom part of the figure are shown the previously reported major mutations in PHF21A gene, in male (blue) and female (pink). The mutation found in our patient is highlighted in yellow. The identified deletions, duplications, and point mutations in the coding sequence are depicted below the exons.