New Deletion of Multiple Genes in the Pathogenic Subtelomeric Region is Related to the Phenotypic Heterogeneity of Patients with Polymalformation Syndrome

Introduction: Genomic testing has advanced significantly, enabling the identification of changes ranging from specific locus modifications to genomic structural alterations. This has improved the diagnosis of diseases and the understanding of little-known genetic disorders. Objective: To describe the case of an adolescent with no consanguineous parents and no family history of genetic variants but with cognitive-behavioral impairment, epilepsy, hypothyroidism, tall stature, and minor facial dysmorphisms suggestive of an overgrowth syndrome. Due to the complexity of the patient's phenotype affecting multiple organs and systems, the patient underwent aCGH analysis to identify deletions or duplications. Methods: Genomic DNA was extracted from a peripheral blood sample of the patient. The DNA was labeled and hybridized using the Agilent® SurePrint G3 Human CGH array 4x180K. The data were scanned and analyzed with the Agilent CytoGenomics v5® software. Results: The aCGH analysis identified a sub-telomeric pathogenic heterozygous deletion in the chromosomal region 5q35.2q35.3. A search was conducted in the Online Mendelian Inheritance in Man, Clinical Genome Resource, and GeneScout databases, where 12 out of 74 genes were associated with medical conditions. Of these, 9 had autosomal recessive inheritance mechanisms and the remaining 3 had autosomal dominant (AD) inheritance. For genes with AD and unclear inheritance mechanisms, and with a high risk of genotype/phenotype correlation (reversed phenotype, crucial for precise diagnosis), a Human Phenotype Ontology search was conducted. This search related the deletion to conditions such as hematological malignancy predisposition syndrome, hereditary angioedema, infantile hypercalcemia 2, Fanconi renotubular syndrome 2, nephrolithiasis/hypophosphatemic osteoporosis 1, Lewy body dementia, and Sotos syndrome. This deletion is associated with a complex phenotype, including autism spectrum disorder and several physical anomalies. Conclusions: Genetic tests such as aCGH are fundamental for diagnosing congenital anomalies and neurodevelopmental disorders. Identifying deletions in the 5q35 region enhances the understanding of polymalformative syndromes and facilitates genetic counseling, thereby improving prognosis and family planning for patients.