A microdeletion involving TNIK is associated with alteration of the Dup(3q) Syndrome phenotype

Duplication 3q Syndrome (Dup (3q)) is a congenital developmental disorder resulting from a duplication of the distal portion of the long arm of chromosome 3. Symptoms include, but are not limited to, craniofacial abnormalities including cleft palate and craniosynotosis, mild upper limb and digital anomalies, delayed skeletal maturation, and mild mental retardation. Due to the large duplication of chromosome 3q that affects multiple genes within the region, Dup (3q) phenotype, has the characteristics of a contiguous gene syndrome. One well characterized patient had an unbalanced 3;22 translocation (46,XY,-22,der(22),t(3;22) (22qter\u3e22p12::3g25.3\u3e3gter), leading to a chromosomal duplication at 3q25.3 to 3qter. This karyotype was consistent with the Dup(3q) syndrome, however, the patient had a more severe phenotype with microbrachycephaly, high arched palate, micrognathia, and profound mental retardation. Comparative Genome Hybridization (CGH) array data confirmed that the region of duplication was similar to other Dup (3q) syndrome patients and therefore unlikely to be responsible for the alteration in phenotype. Fluorescent In Situ Hybridization (FISH) analysis using Bacterial Artifical Chromosomes (BACs) from the chromosome 3q25-3q27 region revealed that the patient had a microdeletion within the region of 3q duplication. Subsequent FISH analysis using subclones of the BACs within the region confirmed and narrowed the microdeletion to the boundary of 3q26-q27. Quantitative analysis of copy number by primer extension (SNuPE) at specific SNP locations within the region of interest revealed that the microdeletion involved only the TRAF2 and NCK-interacting Kinase (TNIK) locus on chromosome 3q26 – q27. The microdeletion generated a genomic imbalance in copy number between TNIK (2 copies) and the remaining chromosome 3q25.1-qter region (3 copies). This microdeletion was not present in Dup(3q) syndrome patients with the milder phenotype. ^ We conclude that the more severe phenotype was the result of the imbalance in copy number between the modifier gene TNIK and the remaining genes within the chromosome 3q duplication. This more severe phenotype of Dup (3q) syndrome is similar to the phenotype of Cornelia de Lange Syndrome (CdLS) patients, a dysmorphology syndrome linked to the NIPBL locus on chromosome 5p13.1. Some CdLS families that do not have mutations in the NIPBL locus but do show linkage to chromosome 3 may be misdiagnosed and instead have severe Dup (3q) syndrome as a result of a genomic imbalance between TNIK and other genes duplicated on chromosome 3q.