Clinical and Cytogenomic Characterization of Three Patients With Distal 1q43q44 Deletion: Twin Sisters With a de novo Deletion and a Patient With der(1)t(1;21)(q43;q22.3)mat.

BACKGROUND: Deletions involving the 1q43q44 region are among the most recurrent terminal chromosomal imbalances and are associated with a recognizable neurodevelopmental phenotype. These deletions may occur as isolated events or in the context of more complex rearrangements. CASE PRESENTATION: We describe presumed monozygotic twin sisters (patients 1 and 2) with a de novo 1q43q44 deletion and an unrelated patient (patient 3) carrying a similar deletion combined with a 21q22.3 duplication derived from a t(1;21)(q43;q22.3)mat. All three patients exhibited features consistent with the distal 1q43q44 deletion syndrome, including microcephaly, corpus callosum abnormalities, developmental delay, intellectual disability, language impairment, hypotonia, micro-/retrognathia, and congenital heart defects. RESULTS: Cytogenetics and FISH analyses confirmed distal 1q deletions in all patients. Chromosomal microarray analysis identified a ~9.5 Mb deletion in patient 1 (her twin was not tested) and a ~12.1 Mb deletion in patient 3. Despite differences in deletion size and genomic context, both rearrangements disrupted a largely overlapping interval containing 171 genes, including the dosage-sensitive neurodevelopmental genes AKT3, HNRNPU, and ZBTB18 as well as other monoallelic expressed genes (GREM2 and NLRP3) and, in patient 3 only, RYR2. Functional enrichment analyses highlighted pathways related to neurodevelopment, epilepsy, and cardiac function. Although the twins showed similar congenital manifestations, patient 1 later developed seizures whose origin could not be assessed. CONCLUSION: These findings further support the role of haploinsufficient genes within the distal 1q43q44 region, particularly AKT3, HNRNPU, and ZBTB18, to the core neurodevelopmental phenotype and highlight the value of high-resolution genomic analysis for patient characterization.