A Homozygous ALCAM-CBLB Deletion at 3q13.11-q13.12 Defines a Candidate Novel Oculo-Skeletal-Immune Contiguous Gene Deletion Syndrome.

Abstract

To our knowledge, we report the first combined homozygous deletion of ALCAM and CBLB at 3q13.11-q13.12. The patient, a 14-year-old boy born to consanguineous parents, had a multisystem phenotype with severe congenital ocular and craniofacial anomalies, early-onset osteoporosis, progressive scoliosis, growth failure, congenital heart defect, humoral immunodeficiency, and chronic inflammatory findings. SNP array identified a 2.5-Mb homozygous deletion spanning ALCAM and CBLB, and expression studies confirmed complete absence of ALCAM and CBLB expression. Whole-exome sequencing did not identify an alternative molecular diagnosis. The clinical presentation is likely attributable to combined ALCAM and CBLB loss. Previous animal-model studies support interpretation of the individual phenotypic components by linking loss of these genes to craniofacial developmental abnormalities, skeletal findings, and immune dysregulation. We propose that this deletion may represent a candidate novel contiguous gene deletion syndrome. This case is the first human phenotype associated with complete ALCAM loss in a contiguous deletion and expands the clinical spectrum associated with disruption of ALCAM and CBLB.