Chromosome 17q12 Duplication Syndrome

A number sign (#) is used with this entry because of evidence that it represents a contiguous gene syndrome caused by duplication at chromosome 17q12 (Chr17:31.5-33.6 Mb, NCBI35).

Molecular Genetics

In 290 individuals with mental retardation, Sharp et al. (2006) used BAC array CGH to investigate 130 candidate chromosomal regions for genomic disorders. They identified a 1.46-Mb duplication at 17q12 in 1 patient with mental retardation, and noted that both breakpoints of the duplication mapped to a pair of 66-kb flanking segmental duplications with 99.7% similarity. The duplication was also detected in an affected sib, but was not found in their unaffected mother.

In a study of chromosomal regions predisposed to recurrent rearrangements, Mefford et al. (2007) identified 2 patients with mild to moderate mental retardation, epilepsy, and focal cortical dysplasia who had overlapping duplications on chromosome 17q12. Oligonucleotide microarray CGH analysis in 1 of these patients and the proband previously studied by Sharp et al. (2006) showed that they had duplications of the entire 17q12 region, with breakpoints mapping to the same duplication blocks associated with renal disease and MODY5 deletions (see 137920). However, this reciprocal duplication of 17q12 was also found in unaffected family members and in 1 of 960 unrelated Caucasian controls, making the pathologic significance of the duplication unclear. The third patient had a smaller and more complex duplication, in which there was a 27-kb duplication encompassing the LHX1 gene (601999) and a 259-kb duplication corresponding to the TCF2 gene (HNF1B; 189907). The patient's unaffected mother carried the TCF2 duplication, and interphase FISH analysis showed her to be mosaic for the LHX1 duplication (28% of 135 nuclei), whereas the patient had the LHX1 duplication in virtually all cells (98% of 138 nuclei).

Mencarelli et al. (2008) used oligonucleotide array CGH to analyze 84 patients with mild to severe mental retardation associated with multiple congenital anomalies and identified a 1.8-Mb duplication at chromosome 17q12 in a 15-year-old boy with XX sex reversal, severe mental retardation, Peters anomaly, microphthalmia, glaucoma, cleft soft palate, atrial septal defect, mild brachydactyly, and fifth finger clinodactyly. His healthy father and a sister with isolated behavioral problems were also carriers of the duplication, which encompassed TCF2 and 18 other genes.

Nagamani et al. (2010) studied 9 patients with genomic rearrangements in chromosome 17q12, including 4 patients with a deletion (see 614527) and 5 with a duplication. The 5 patients with a duplication all presented with cognitive impairment except 1, who had nonsyndromic esophageal atresia, age-appropriate development, normal renal function and imaging, and no diabetes; information on renal status and diabetes in the other 4 patients was not available. The duplications in all 5 patients encompassed a minimum of 1.06 Mb from the LHX1 gene to LOC28400, and a possible maximum of 2.46 Mb, extending from the CCL3L3 gene (609468) to the SNIP gene (610786).

Caselli et al. (2010) reported a 6-year-old boy with mental retardation and a 12.4-Mb duplication of chromosome 17q11.2-q12, encompassing the NF1 gene (613113) and about 130 additional genes. Unilateral megacalicosis of the left kidney had been seen on prenatal ultrasound and was confirmed at 1 year of age; cerebral MRI at that time showed a thin corpus callosum. Dysmorphic features included dolichocephaly and a triangular, hypotonic face with deep-set eyes and downslanting palpebral fissures, large and anteverted ears, smooth philtrum, and micrognathia. He also displayed rotational tongue movements, axial hypotonia, and had short second fingers bilaterally and broad thumbs and toes. Caselli et al. (2010) stated that the description of additional cases is essential to delineate a specific phenotype for chromosome 17q11.2-q12 duplication.

Kaminsky et al. (2011) presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. Compared with controls, 14 deletions and 7 duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. The 17q12 duplication was identified in 21 cases and 4 controls for a p value of 0.022 and a frequency of 1 in 750 cases.