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

INTRODUCTION: 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. CASE 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. CONCLUSION: 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.