We present prenatal diagnosis of a 14-Mb 11p11.2-p13 deletion by chromosome microarray analysis (CMA) in a pregnancy with fetal recombinant chromosome 11 syndrome of rec(11)del(11) (p11.2p13)ins(11) (q21p11.2p13) and maternal intrachromosomal insertion of ins(11) (q21p11.2p13). A 25-year-old, primigravid woman underwent amniocentesis at 17 weeks of gestation because of a family history of psychiatric disorders in her two brothers and one maternal uncle. Array comparative genomic hybridization (aCGH) analysis of amniocentesis revealed a 14-Mb 11p13p11.2 deletion. The pregnancy was terminated at 19 weeks of gestation, and a 252-g fetus was delivered. Cytogenetic analysis of the parental bloods and cord blood revealed a karyotype of 46,XX,ins(11) (q21p11.2p13) in the mother, 46,XY in the father and 46,XY,rec(11)del(11) (p11.2p13)ins(11) (q21p11.2p13) in the fetus. aCGH analysis on the DNA extracted from cord blood revealed the result of arr 11p13q11.2 (32,697,424-46,712,173) × 1.0 [GRCh37] with a 14-Mb deletion of 11p13-p11.2 encompassing 54 OMIM genes including PHF21A, ALX4, EXT2 and SLC1A2. Polymorphic DNA marker analysis showed a maternal origin of the 11p deletion. The present case had an 11p13-p11.2 deletion encompassing 11p12-p11.3 which is associated with Potocki-Shaffer syndrome (PSS) or chromosome 11p11.2 deletion syndrome. CMA is useful for prenatal detection of fetal genomic imbalance in case of familial intrachromosomal insertion.

Potocki-Shaffer syndrome (PSS) is a rare neurodevelopmental disorder caused by deletions involving the 11p11.2-p12 region, encompassing the plant homeodomain finger protein 21A (PHF21A) gene. PHF21A has an important role in epigenetic regulation and PHF21A variants have previously been associated with a specific disorder that, whilst sharing some features of PSS, has notable differences. This study aims to expand the phenotype, particularly in relation to overgrowth, associated with PHF21A variants. Analysis of phenotypic data was undertaken on 13 individuals with PHF21A constitutional variants including four individuals described in the current series. Of those individuals where data were recorded, postnatal overgrowth was reported in 5/6 (83%). In addition, all had both an intellectual disability and behavioural issues. Frequent associations included postnatal hypotonia (7/11, 64%); and at least one afebrile seizure episode (6/12, 50%). Although a recognizable facial gestalt was not associated, subtle dysmorphic features were shared amongst some individuals and included a tall broad forehead, broad nasal tip, anteverted nares and full cheeks. We provide further insight into the emerging neurodevelopmental syndrome associated with PHF21A disruption. We present some evidence that PHF21A might be considered a new member of the overgrowth-intellectual disability syndrome (OGID) family.

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.

PHF21A, along with EXT2 and ALX4, is one of the causative genes of Potocki-Shaffer syndrome (PSS), a rare contiguous disorder involving chromosome region11p11.2. PHF21A has been associated with intellectual developmental disorders and craniofacial anomalies and suggested as a candidate for more extended phenotypes. However, variants in PHF21A and its associated phenotypes are yet to be fully explored, since reports on cases with variants affecting this gene are few worldwide. We present a novel heterogeneous variant in PHF21A in a 26-year-old Korean female. The patient's clinical manifestations were recorded and physical examination, cognitive assessment, brain imaging, metabolic screening, and cytogenetic testing including whole exome sequencing were pursued. Whole exome sequencing identified a de novo nonsense variant c.1171A>T (p.Lys391Ter), affecting the AT-hook domain. The patient showed an extended phenotypic spectrum along with intellectual developmental disorders and craniofacial anomalies, such as attention-deficit hyperactivity disorder, epilepsy, overgrowth, and hypotonia. Variants affecting the AT-hook domain are few in PSS, however, the phenotypic spectrum of the patient was in line with previously reported cases. This case further reinforced and adds to the extended data on the phenotypes associated with PHF21A haploinsufficiency.