17p11.2p12 triplication and del(17)q11.2q12 in a severely affected child with dup(17)p11.2p12 syndrome

Abstract

Multiple congenital anomalies/mental retardation syndromes due to genomic rearrangements involving chromosome 17p11.2 include deletion resulting in Smith-Magenis syndrome and a reciprocal duplication of the same region resulting in the 17p11.2 duplication syndrome. We present the clinical and molecular analysis of an 8-year-old male with a dup(17p11.2p12) who was evaluated for unusual severity of the phenotype. Fluorescent in situ hybridization (FISH) analysis not only confirmed the 17p duplication but also identified an approximately 25% mosaicism for tetrasomy 17p11.2p12. Whole-genome array comparative genomic hybridization (aCGH) was performed to identify other genomic rearrangements possibly contributing to the severe phenotype and the unusual features in the patient. The 17p duplication was determined by FISH and aCGH to encompass approximately 7.5 Mb, from COX10 to KCNJ12. An approximately 830 Kb deletion of 17q11.2q12, including exon 1 of an amiloride-sensitive cation channel neuronal gene, ACCN1, was also identified by aCGH; breakpoints of the deletion were confirmed by FISH. Sequencing the non-deleted allele of ACCN1 did not show any mutations. Western analysis of human tissue-specific proteins revealed that ACCN1 is expressed not only in the brain as previously reported but also in all tissues examined, including heart, liver, kidneys, and spleen. The large-sized 17p11.2p12 duplication, partial triplication of the same region, and the 17q11.2q12 deletion create a complex chromosome 17 rearrangement that has not been previously identified. This is the first case of triplication reported for this chromosome. Our study emphasizes the utility of whole-genome analysis for known cases with deletion/duplication syndromes with unusual or severe phenotypes.

How much is too much? Phenotypic consequences of Rai1 overexpression in mice

“…Patients with SMS as well as individuals with dup(17)(p11.2) syndrome have a definitive delay in growth during early childhood. 1,4 The growth deficiency observed in the transgenic animals is possibly due to an involvement of Rai1 in body energy and metabolic regulation; however, feeding behavior, neural regulation, and pituitary control of somatic growth cannot be ruled out. 35 Since Rai1 þ /À mice are obese and those overexpressing Rai1 are lean and growth retarded, mirroring the phenotypes observed in the corresponding human syndromes, there appears to be a direct correlation between Rai1 dosage and body mass, pointing to a conserved regulatory pathway between mouse and human.…”

“…2,4 Patients with dup(17)(p11.2) syndrome present with mental retardation, preand postnatal growth retardation, cognitive impairment, craniofacial abnormalities, heart defects, and hyperactivity. 1,5 More than 40 patients with dup(17)(p11.2p11.2), ranging from 1.3 to 15 Mb in size, have been described. 1,5 The critical region for the duplication has been narrowed down to approximately 1.3 Mb and also contains RAI1.…”

“…1,5 The critical region for the duplication has been narrowed down to approximately 1.3 Mb and also contains RAI1. 1,5 So, it is likely that RAI1 plays a dosage-sensitive role contributing to both SMS and dup(17)(p11.2) syndrome.…”

“…1,2 SMS is characterized by mental retardation, craniofacial and skeletal abnormalities, speech and motor delays, sleep abnormalities, neurological and behavioral features, and obesity. 3 Recently, we determined that haploinsufficiency of RAI1 is responsible for most SMS features, while other genes in the SMS region contribute to the more variable features and overall severity of the phenotype.…”

CHRNA7 triplication associated with cognitive impairment and neuropsychiatric phenotypes in a three-generation pedigree

“…15 In general, the resulting clinical phenotype is consistent with, but more severe than, the duplication of the same locus. 12,14,[16][17][18] Triplications of genomic loci associated with neurocognitive and neuropsychiatric abnormalities have been described, among others, at 22q11.2, 18 7p11.2, 19 Xq28 encompassing the MECP2 gene, 20 and 7q11.23 at the Williams syndrome critical region. 17 Triplications can, in general, be classified as types I and II, as well as being recurrent or non-recurrent, which relates to the molecular mechanism underlying their formation.…”