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Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant.
- Source :
-
Journal of medical genetics [J Med Genet] 2009 Apr; Vol. 46 (4), pp. 223-32. Date of Electronic Publication: 2008 Jun 11. - Publication Year :
- 2009
-
Abstract
- Background: Genomic disorders are often caused by non-allelic homologous recombination between segmental duplications. Chromosome 16 is especially rich in a chromosome-specific low copy repeat, termed LCR16.<br />Methods and Results: A bacterial artificial chromosome (BAC) array comparative genome hybridisation (CGH) screen of 1027 patients with mental retardation and/or multiple congenital anomalies (MR/MCA) was performed. The BAC array CGH screen identified five patients with deletions and five with apparently reciprocal duplications of 16p13 covering 1.65 Mb, including 15 RefSeq genes. In addition, three atypical rearrangements overlapping or flanking this region were found. Fine mapping by high-resolution oligonucleotide arrays suggests that these deletions and duplications result from non-allelic homologous recombination (NAHR) between distinct LCR16 subunits with >99% sequence identity. Deletions and duplications were either de novo or inherited from unaffected parents. To determine whether these imbalances are associated with the MR/MCA phenotype or whether they might be benign variants, a population of 2014 normal controls was screened. The absence of deletions in the control population showed that 16p13.11 deletions are significantly associated with MR/MCA (p = 0.0048). Despite phenotypic variability, common features were identified: three patients with deletions presented with MR, microcephaly and epilepsy (two of these had also short stature), and two other deletion carriers ascertained prenatally presented with cleft lip and midline defects. In contrast to its previous association with autism, the duplication seems to be a common variant in the population (5/1682, 0.29%).<br />Conclusion: These findings indicate that deletions inherited from clinically normal parents are likely to be causal for the patients' phenotype whereas the role of duplications (de novo or inherited) in the phenotype remains uncertain. This difference in knowledge regarding the clinical relevance of the deletion and the duplication causes a paradigm shift in (cyto)genetic counselling.
- Subjects :
- Abnormalities, Multiple pathology
Adult
Aged
Chromosome Deletion
Chromosome Disorders genetics
Chromosome Disorders pathology
Cleft Lip pathology
Comparative Genomic Hybridization
Epilepsy pathology
Gene Duplication
Growth Disorders pathology
Humans
Intellectual Disability pathology
Microcephaly pathology
Middle Aged
Phenotype
Polymorphism, Single Nucleotide
Reverse Transcriptase Polymerase Chain Reaction
Risk Factors
Abnormalities, Multiple genetics
Chromosome Aberrations
Chromosomes, Human, Pair 16 genetics
Intellectual Disability genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1468-6244
- Volume :
- 46
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of medical genetics
- Publication Type :
- Academic Journal
- Accession number :
- 18550696
- Full Text :
- https://doi.org/10.1136/jmg.2007.055202