3.7 Mb tandem microduplication in chromosome 5p13.1-p13.2 associated with developmental delay, macrocephaly, obesity, and lymphedema. Further characterization of the dup(5p13) syndrome.

In a male patient with developmental delay, autistic behaviour, obesity, lymphedema, hypertension, macrocephaly, and facial features of chromosome 5p duplication (trisomy 5p) a 3.7 Mb de novo tandem microduplication of 5p13.1-13.2 (rs4703415-rs261752, i.e., chr5:35.62-39.36 Mb) was identified. This observation contributes to the characterization and dissection of the 5p13 duplication syndrome. The possible role of increased NIPBL gene dosage is discussed.

Cohen syndrome diagnosis using whole genome arrays.

BACKGROUND: Cohen syndrome is a rare autosomal recessive disorder with a complex phenotype including psychomotor retardation, microcephaly, obesity with slender extremities, joint laxity, progressive chorioretinal dystrophy/myopia, intermittent isolated neutropenia, a cheerful disposition, and characteristic facial features. The COH1 gene, which contains 62 exons, is so far the only gene known to be associated with Cohen syndrome. Point mutations, deletions and duplications have been described in this gene. Oligonucleotide arrays have reached a resolution which allows the detection of intragenic deletions and duplications, especially in large genes such as COH1. METHOD AND RESULTS: High density oligonucleotide array data from patients with unexplained mental retardation (n=1523) and normal controls (n=1612) were analysed for copy number variation (CNV) changes. Intragenic heterozygous deletions in the COH1 gene were detected in three patients but no such changes were detected in the controls. Subsequent sequencing of the COH1 gene revealed point mutations in the second allele in all three patients analysed. CONCLUSION: Genome-wide CNV screening with high density arrays provides a tool to detect intragenic deletions in the COH1 gene. This report presents an example of how microarrays can be used to identify autosomal recessive syndromes and to extend the phenotypic and mutational spectrum of recessive disorders.

Identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits.

Mental retardation affects 2-3% of the population and shows a high heritability.Neurodevelopmental disorders that include pronounced impairment in language and speech skills occur less frequently. For most cases, the molecular basis of mental retardation with or without speech and language disorder is unknown due to the heterogeneity of underlying genetic factors.We have used molecular karyotyping on 1523 patients with mental retardation to detect copy number variations (CNVs) including deletions or duplications. These studies revealed three heterozygous overlapping deletions solely affecting the forkhead box P1 (FOXP1) gene. All three patients had moderate mental retardation and significant language and speech deficits. Since our results are consistent with a de novo occurrence of these deletions, we considered them as causal although we detected a single large deletion including FOXP1 and additional genes in 4104 ancestrally matched controls. These findings are of interest with regard to the structural and functional relationship between FOXP1 and FOXP2. Mutations in FOXP2 have been previously related to monogenic cases of developmental verbal dyspraxia. Both FOXP1 and FOXP2 are expressed in songbird and human brain regions that are important for the developmental processes that culminate in speech and language.

Microdeletion syndrome 16p11.2-p12.2: clinical and molecular characterization.

The pericentromeric region on 16p appears to be susceptible to chromosomal rearrangements and several patients with rearrangements in this region have been described. We report on a further patient with a microdeletion 16p11.2-p12.2 in the context of described patients with a deletion in the pericentromeric region of 16p. Minor facial anomalies, feeding difficulties, significant delay in speech development, and recurrent ear infections are common symptoms of the microdeletion syndrome 16p11.2-p12.2. All reported patients so far share a common distal breakpoint at 16p12.2 but vary in the proximal breakpoint at 16p11.2. The microdeletion 16p11.2-p12.2 should be distinguished from the approximately 500 kb microdeletion in 16p11.2 which seems to be associated with autism but not with facial manifestations, feeding difficulties, or developmental delay.

Copy number variation at the 7q11.23 segmental duplications is a susceptibility factor for the Williams-Beuren syndrome deletion.

Large copy number variants (CNVs) have been recently found as structural polymorphisms of the human genome of still unknown biological significance. CNVs are significantly enriched in regions with segmental duplications or low-copy repeats (LCRs). Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by a heterozygous deletion of contiguous genes at 7q11.23 mediated by nonallelic homologous recombination (NAHR) between large flanking LCRs and facilitated by a structural variant of the region, a approximately 2-Mb paracentric inversion present in 20%-25% of WBS-transmitting progenitors. We now report that eight out of 180 (4.44%) WBS-transmitting progenitors are carriers of a CNV, displaying a chromosome with large deletion of LCRs. The prevalence of this CNV among control individuals and non-transmitting progenitors is much lower (1%, n=600), thus indicating that it is a predisposing factor for the WBS deletion (odds ratio 4.6-fold, P= 0.002). LCR duplications were found in 2.22% of WBS-transmitting progenitors but also in 1.16% of controls, which implies a non-statistically significant increase in WBS-transmitting progenitors. We have characterized the organization and breakpoints of these CNVs, encompassing approximately 100-300 kb of genomic DNA and containing several pseudogenes but no functional genes. Additional structural variants of the region have also been defined, all generated by NAHR between different blocks of segmental duplications. Our data further illustrate the highly dynamic structure of regions rich in segmental duplications, such as the WBS locus, and indicate that large CNVs can act as susceptibility alleles for disease-associated genomic rearrangements in the progeny.