Novel Pathogenic Variant (c.1171A>T) in PHF21A in a Female with Intellectual Disability and Craniofacial Anomalies

Area of Science:

• Genetics
• Developmental Biology
• Medical Genetics

Background:

• PHF21A is a causative gene for Potocki-Shaffer syndrome (PSS), a rare disorder affecting chromosome region 11p11.2.
• PHF21A variants are linked to intellectual disability and craniofacial anomalies, with potential for broader phenotypic expression.
• Limited global case reports necessitate further exploration of PHF21A variants and their associated phenotypes.

Purpose of the Study:

• To report a novel PHF21A variant in a Korean female patient.
• To characterize the extended phenotypic spectrum associated with PHF21A haploinsufficiency.
• To contribute to the understanding of Potocki-Shaffer syndrome genetics.

Main Methods:

• Clinical manifestations were documented.
• Comprehensive assessments included physical examination, cognitive evaluation, brain imaging, metabolic screening, and cytogenetic testing.
• Whole exome sequencing (WES) was performed to identify genetic variants.

Main Results:

• Whole exome sequencing identified a de novo nonsense variant (c.1171A>T, p.Lys391Ter) in the PHF21A gene, affecting the AT-hook domain.
• The patient presented with an extended phenotype including intellectual developmental disorders, craniofacial anomalies, ADHD, epilepsy, overgrowth, and hypotonia.
• The observed phenotypic spectrum aligns with previously reported cases, despite the rarity of AT-hook domain variants in PSS.

Conclusions:

• This case reinforces and expands the known phenotypic spectrum associated with PHF21A haploinsufficiency.
• The findings highlight the importance of considering PHF21A in patients with complex developmental disorders.
• Further research is warranted to fully elucidate the genotype-phenotype correlations of PHF21A variants.