Recurrent Rearrangements of Chromosome 1q21.1 and Variable Pediatric Phenotypes

University of Washington School of Medicine, Seattle 98195, USA.
New England Journal of Medicine (Impact Factor: 55.87). 10/2008; 359(16):1685-99. DOI: 10.1056/NEJMoa0805384
Source: PubMed


Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients.
We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons.
We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P=1.1x10(-7)). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P=0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies.
We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype.

Download full-text


Available from: Corrado Romano,
79 Reads
  • Source
    • "Multiple independent reports have shown that deletions and duplications in 1q21 are associated with microcephaly and macrocephaly, respectively (Brunetti-Pierri et al., 2008; Mefford et al., 2008). These findings strongly suggest that the copy number of one or more sequences in this region is directly influencing human brain size. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Here we present the hypothesis that increasing copy number (dosage) of sequences encoding DUF1220 protein domains is a major contributor to the evolutionary increase in brain size, neuron number, and cognitive capacity that is associated with the primate order. We further propose that this relationship is restricted to the anthropoid sub-order of primates, with DUF1220 copy number markedly increasing in monkeys, further in apes, and most extremely in humans where the greatest number of copies (~272 haploid copies) is found. We show that this increase closely parallels the increase in brain size and neuron number that has occurred among anthropoid primate species. We also provide evidence linking DUF1220 copy number to brain size within the human species, both in normal populations and in individuals associated with brain size pathologies (1q21-associated microcephaly and macrocephaly). While we believe these and other findings presented here strongly suggest increase in DUF1220 copy number is a key contributor to anthropoid brain expansion, the data currently available rely largely on correlative measures that, though considerable, do not yet provide direct evidence for a causal connection. Nevertheless, we believe the evidence presented is sufficient to provide the basis for a testable model which proposes that DUF1220 protein domain dosage increase is a main contributor to the increase in brain size and neuron number found among the anthropoid primate species and that is at its most extreme in human.
    Frontiers in Human Neuroscience 06/2014; 8:427. DOI:10.3389/fnhum.2014.00427 · 3.63 Impact Factor
  • Source
    • "The duplication spanned the 1q21.1 distal region but did not include the TAR (thrombocytopenia with absent radius) syndrome region. The size of this duplication is larger than many of the cases described by Brunetti et al. [25] and Mefford et al. [26] but is similar to other recently reported cases [27]. The probe coverage may contribute to the discrepancy for the estimated size of duplication in different reports. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Infantile spasms (IS) is a specific type of epileptic encephalopathy associated with severe developmental disabilities. Genetic factors are strongly implicated in IS, however, the exact genetic defects remain unknown in the majority of cases. Rare mutations in a single gene or in copy number variants (CNVs) have been implicated in IS of children in Western countries. The objective of this study was to dissect the role of copy number variations in Chinese children with infantile spasms. Methods We used the Agilent Human Genome CGH microarray 180 K for genome-wide detection of CNVs. Real-time qPCR was used to validate the CNVs. We performed genomic and medical annotations for individual CNVs to determine the pathogenicity of CNVs related to IS. Results We report herein the first genome-wide CNV analysis in children with IS, detecting a total of 14 CNVs in a cohort of 47 Chinese children with IS. Four CNVs (4/47 = 8.5%) (1q21.1 gain; 1q44, 2q31.1, and 17p13 loss) are considered to be pathogenic. The CNV loss at 17p13.3 contains PAFAH1B1 (LIS1), a causative gene for lissencephaly. Although the CNVs at 1q21.1, 1q44, and 2q23.1 have been previously implicated in a wide spectrum of clinical features including autism spectrum disorders (ASD) and generalized seizure, our study is the first report identifying them in individuals with a primary diagnosis of IS. The CNV loss in the 1q44 region contains HNRNPU, a strong candidate gene recently suggested in IS by the whole exome sequencing of children with IS. The CNV loss at 2q23.1 includes MBD5, a methyl-DNA binding protein that is a causative gene of ASD and a candidate gene for epileptic encephalopathy. We also report a distinct clinical presentation of IS, microcephaly, intellectual disability, and absent hallux in a case with the 2q23.1 deletion. Conclusion Our findings strongly support the role of CNVs in infantile spasms and expand the clinical spectrum associate with 2q23.1 deletion. In particular, our study implicates the HNRNPU and MBD5 genes in Chinese children with IS. Our study also supports that the molecular mechanisms of infantile spasms appear conserved among different ethnic backgrounds.
    BMC Medical Genetics 05/2014; 15(1):62. DOI:10.1186/1471-2350-15-62 · 2.08 Impact Factor
  • Source
    • "the last decade are having a significant impact on our understanding of different disorders . Genetic studies show that disorders , which have formerly been defined as clinically distinct disorders ( including schizophrenia , ASD , epilepsy , ID ) share similarities in neurodevelopmental pathology ( Friedman et al . 2008 ; Guilmatre et al . 2009 ; Mefford et al . 2008 ; Stoll et al . 2013 ) . Moreover , epidemiological studies show that these disorders also cluster in families ( Daniels et al . 2008 ; Jokiranta et al . 2013 ; Qin et al . 2005 ) . Even though ASD and epilepsy are now defined as clinically distinct disorders , the strong association between them suggests that also they might share comm"
    [Show abstract] [Hide abstract]
    ABSTRACT: The present population-based study examines associations between epilepsy and autism spectrum disorders (ASD). The cohort includes register data of 4,705 children born between 1987 and 2005 and diagnosed as cases of childhood autism, Asperger's syndrome or pervasive developmental disorders-not otherwise specified. Each case was matched to four controls by gender, date of birth, place of birth, and residence in Finland. Epilepsy was associated with ASD regardless of the subgroup after adjusting for covariates. The associations were stronger among cases with intellectual disability, especially among females. Epilepsy's age at onset was similar between the cases and controls regardless of the ASD subgroup. These findings emphasize the importance to examine the neurodevelopmental pathways in ASD, epilepsy and intellectual disability.
    Journal of Autism and Developmental Disorders 05/2014; 44(10). DOI:10.1007/s10803-014-2126-6 · 3.06 Impact Factor
Show more