Infantile 22q11.2 deletion syndrome with secondary monogenic variants following inconclusive whole exome sequencing: a case report

Abstract

Chromosome 22q11.2 deletion syndrome (22q11.2DS), historically known as DiGeorge syndrome, is a common microdeletion disorder characterized by a wide range of multisystem manifestations. While Whole Exome Sequencing (WES) is increasingly used as a first-tier diagnostic tool for complex infant presentations, it has limited sensitivity for detecting copy-number variants such as microdeletions. Parental consanguinity adds further diagnostic complexity by increasing the likelihood of co-occurring single-gene variants. We present the case of a 12-month-old female born to first-cousin consanguineous parents who presented in early infancy with feeding difficulties, severe growth failure, conotruncal/septal cardiac anomalies (atrial septal defect, pulmonary stenosis, depressed ejection fraction), severe primary hypoparathyroidism with hypocalcemic tetany, and recurrent sepsis. Initial diagnostic WES identified single-nucleotide variants in cardiomyopathy-associated genes (TTN and NEXN) alongside an incidental pathogenic variant in ANO5, but failed to detect a microdeletion. A subsequent, clinically directed Fluorescence In Situ Hybridization (FISH) study using the 22q11 “N25” probe established the definitive diagnosis of 22q11.2 microdeletion. Multidisciplinary management including enteral calcium/vitamin D supplementation, heart failure pharmacotherapy, infection prophylaxis, and deferral of live vaccines resulted in clinical and biochemical stabilization. This case highlights the classic expanded phenotype of 22q11.2DS in infancy and demonstrates the technical limitations of WES in identifying microdeletions. It also illustrates how parental consanguinity can introduce overlapping or incidental genetic findings (TTN, NEXN, ANO5) that require careful clinical correlation. Clinicians must maintain a high index of suspicion for 22q11.2DS based on core clinical features (hypocalcemia, cardiac defects, dysmorphism), as a non-diagnostic or partially explanatory WES result does not rule out microdeletion syndromes. Targeted cytogenetic testing (e.g., FISH or chromosomal microarray) remains essential when microdeletion syndromes are clinically suspected.