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Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities.

ABSTRACT: Chromosome region 1q21.1 contains extensive and complex low-copy repeats, and copy number variants (CNVs) in this region have recently been reported in association with congenital heart defects, developmental delay, schizophrenia and related psychoses. We describe 21 probands with the 1q21.1 microdeletion and 15 probands with the 1q21.1 microduplication. These CNVs were inherited in most of the cases in which parental studies were available. Consistent and statistically significant features of microcephaly and macrocephaly were found in individuals with microdeletion and microduplication, respectively. Notably, a paralog of the HYDIN gene located on 16q22.2 and implicated in autosomal recessive hydrocephalus was inserted into the 1q21.1 region during the evolution of Homo sapiens; we found this locus to be deleted or duplicated in the individuals we studied, making it a probable candidate for the head size abnormalities observed. We propose that recurrent reciprocal microdeletions and microduplications within 1q21.1 represent previously unknown genomic disorders characterized by abnormal head size along with a spectrum of developmental delay, neuropsychiatric abnormalities, dysmorphic features and congenital anomalies. These phenotypes are subject to incomplete penetrance and variable expressivity.

SUBMITTER: Brunetti-Pierri N

PROVIDER: S-EPMC2680128 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities.

Brunetti-Pierri Nicola N Berg Jonathan S JS Scaglia Fernando F Belmont John J Bacino Carlos A CA Sahoo Trilochan T Lalani Seema R SR Graham Brett B Lee Brendan B Shinawi Marwan M Shen Joseph J Kang Sung-Hae L SH Pursley Amber A Lotze Timothy T Kennedy Gail G Lansky-Shafer Susan S Weaver Christine C Roeder Elizabeth R ER Grebe Theresa A TA Arnold Georgianne L GL Hutchison Terry T Reimschisel Tyler T Amato Stephen S Geragthy Michael T MT Innis Jeffrey W JW Obersztyn Ewa E Nowakowska Beata B Rosengren Sally S SS Bader Patricia I PI Grange Dorothy K DK Naqvi Sayed S Garnica Adolfo D AD Bernes Saunder M SM Fong Chin-To CT Summers Anne A Walters W David WD Lupski James R JR Stankiewicz Pawel P Cheung Sau Wai SW Patel Ankita A

Nature genetics 20081201 12

Chromosome region 1q21.1 contains extensive and complex low-copy repeats, and copy number variants (CNVs) in this region have recently been reported in association with congenital heart defects, developmental delay, schizophrenia and related psychoses. We describe 21 probands with the 1q21.1 microdeletion and 15 probands with the 1q21.1 microduplication. These CNVs were inherited in most of the cases in which parental studies were available. Consistent and statistically significant features of m ...[more]

PMID: 19029900

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Project description:BackgroundGenomic 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.Methods and resultsA 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%).ConclusionThese 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.

Dataset Information

Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities.

Publications

Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities.

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