A HECW2 Missense Variant with a Coexisting 15q25.2-q25.3 Deletion: A Dual Molecular Diagnosis Case Report

Dual molecular diagnoses are increasingly recognized with expanded genomic testing, and may result in blended phenotypes when two independent pathogenic findings contribute to the clinical presentation.

A 3-year-old female patient presented with seizures beginning at 8 months of age (generalized tonic-clonic), severe global developmental delay/intellectual disability, generalized hypotonia, absent meaningful speech, and microcephaly (head circumference 44.1 cm, <3rd percentile). Craniofacial features included midface retrusion/hypoplasia, thick eyebrows, bilateral epicanthal folds, upslanting palpebral fissures, large ears, a wide mouth, a full lower lip, and a low posterior hairline. Electroencephalography showed age-inappropriate background activity with frequent high-amplitude bifrontal spike-slow wave discharges that often generalized and occasionally displayed a hypsarrhythmia-like pattern. Cranial magnetic resonance imaging was reported as showing a mega cisterna magna variation.

Exome sequencing (ES) identified a heterozygous missense variant in HECW2, NM_001348768.2:c.4485G>T p.(Arg1495Ser). Copy-number variant (CNV) analysis of the ES data detected an approximately 2.6 megabase (Mb) heterozygous deletion on chromosome 15, subsequently confirmed by chromosomal microarray analysis as a 2.79 Mb 15q25.2-q25.3 deletion and classified as pathogenic according to American College of Medical Genetics and Genomics/Clinical Genome Resource (ACMG/ClinGen) technical standards. Both alterations were de novo. This case represents a rare dual molecular diagnosis involving a HECW2 missense variant and a 15q25.2-q25.3 deletion, supporting a potential blended phenotype and expanding the molecular and phenotypic spectrum of HECW2-related neurodevelopmental disorder.