Microduplication of 3p26.3 in Nonsyndromic Intellectual Disability Indicates an Important Role of CHL1 for Normal Cognitive Function

Abstract

Terminal deletions of chromosome 3p26.3 confined to the CHL1 gene have previously been described in children with intellectual disability and epilepsy. Here, we report for the first time, a 3p26.3 duplication including only the CHL1 gene in an intellectually disabled girl with epilepsy. The penetrance of both deletions and duplications in 3p26.3 is reduced because all chromosomal imbalances were inherited from healthy parents. Further studies are needed to specify the pathogenic mechanism of 3p26.3 imbalances and to estimate recurrence risks in genetic counseling. However, the description of both deletions and duplications of chromosome 3p26.3 in nonsyndromic intellectual disability suggests that CHL1 is a dosage-sensitive gene with an important role for normal cognitive development.

Keywords

chromosomal duplication - intellectual disability - epilepsy - CHL1 gene

• References

• 1 Malmgren H, Sahlén S, Wide K, Lundvall M, Blennow E. Distal 3p deletion syndrome: detailed molecular cytogenetic and clinical characterization of three small distal deletions and review. Am J Med Genet A 2007; 143A (18) 2143-2149
• 2 Takagishi J, Rauen KA, Drumheller T, Kousseff B, Sutcliffe M. Chromosome 3p25 deletion in mother and daughter with minimal phenotypic effect. Am J Med Genet A 2006; 140 (14) 1587-1593
• 3 Cuoco C, Ronchetto P, Gimelli S , et al. Microarray based analysis of an inherited terminal 3p26.3 deletion, containing only the CHL1 gene, from a normal father to his two affected children. Orphanet J Rare Dis 2011; 6: 12-15
• 4 Angeloni D, Lindor NM, Pack S, Latif F, Wei MH, Lerman MI. CALL gene is haploinsufficient in a 3p- syndrome patient. Am J Med Genet 1999; 86 (5) 482-485
• 5 Frints SG, Marynen P, Hartmann D , et al. CALL interrupted in a patient with non-specific mental retardation: gene dosage-dependent alteration of murine brain development and behavior. Hum Mol Genet 2003; 12 (13) 1463-1474
• 6 Pohjola P, de Leeuw N, Penttinen M, Kääriäinen H. Terminal 3p deletions in two families—correlation between molecular karyotype and phenotype. Am J Med Genet A 2010; 152A (2) 441-446
• 7 Leshchyns'ka I, Sytnyk V, Richter M, Andreyeva A, Puchkov D, Schachner M. The adhesion molecule CHL1 regulates uncoating of clathrin-coated synaptic vesicles. Neuron 2006; 52 (6) 1011-1025
• 8 Kenwrick S, Watkins A, De Angelis E. Neural cell recognition molecule L1: relating biological complexity to human disease mutations. Hum Mol Genet 2000; 9 (6) 879-886
• 9 Jouet M, Rosenthal A, Armstrong G , et al. X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. Nat Genet 1994; 7 (3) 402-407
• 10 Merla G, Brunetti-Pierri N, Micale L, Fusco C. Copy number variants at Williams-Beuren syndrome 7q11.23 region. Hum Genet 2010; 128 (1) 3-26
• 11 Kurth I, Klopocki E, Stricker S , et al. Duplications of noncoding elements 5′ of SOX9 are associated with brachydactyly-anonychia. Nat Genet 2009; 41 (8) 862-863
• 12 Wagner T, Wirth J, Meyer J , et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9 . Cell 1994; 79 (6) 1111-1120
• 13 Barber JC. Directly transmitted unbalanced chromosome abnormalities and euchromatic variants. J Med Genet 2005; 42 (8) 609-629