Phenotype-genotype characterization of alpha-thalassemia mental retardation syndrome due to isolated monosomy of 16p13.3

Abstract

An 8-year-old Caucasian girl presented with mild dysmorphic features and intellectual disability (ID) affecting multiple spheres. Dysmorphisms included a high forehead with up-slanting palpebral fissures, prominent nasal root and bridge, flattened maxilla, high-arched palate, and anterior frenulum. Structural brain anomalies included reduced periventricular white matter volume and thin corpus callosum. The presence of HbH bodies and her clinical presentation raised suspicion for autosomal alpha-thalassemia mental retardation syndrome (ATR-16). Whole-genome array analysis at 1 Mb resolution was performed, which revealed a sub-microscopic loss of 16p involving clones RP11-344L6 at 0.1 Mb, RP1-121I4 at 0.2 Mb and RP11-334D3 at 1 Mb. FISH confirmed deletion (del) of the terminal clone (RP1-121I4) on 16pter, which was de novo in origin. The more proximal clone RP11-334D3 (at 1 Mb) showed diminished FISH signal intensity on one of the homologues, suggesting that one breakpoint occurred within this clone. Quantitative PCR (qPCR) confirmed a de novo deletion encompassing SOX8 (at 0.97 Mb). ATR-16 is characterized by ID with mild, nonspecific dysmorphic features, and is associated with terminal del16p (MIM No. 141750). Cases of isolated monosomy for 16p are rarely described; such descriptions help to delineate the syndrome in the absence of confounding karyotypic anomalies. We describe detailed molecular cytogenetic and clinical findings relating to a subject with ATR-16.