Wiszniewski W.,Baylor College of Medicine |
Hunter J.V.,Texas Childrens Hospital |
Hanchard N.A.,Baylor College of Medicine |
Willer J.R.,Duke University |
And 62 more authors.
American Journal of Human Genetics | Year: 2013
White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ∼70% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles. © 2013 The American Society of Human Genetics.
Dharmadhikari A.V.,Baylor College of Medicine |
Gambin T.,Baylor College of Medicine |
Szafranski P.,Baylor College of Medicine |
Cao W.,Baylor College of Medicine |
And 16 more authors.
BMC Medical Genetics | Year: 2014
Background: Point mutations or genomic deletions of result in a lethal developmental lung disease Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. However, the clinical consequences of the constitutively increased dosage of are unknown. Methods: Copy-number variations and their parental origin were identified using a combination of array CGH, long-range PCR, DNA sequencing, and microsatellite analyses. Minisatellite sequences across different species were compared using a gready clustering algorithm and genome-wide analysis of the distribution of minisatellite sequences was performed using R statistical software. Results: We report four unrelated families with 16q24.1 duplications encompassing entire . In a 4-year-old boy with speech delay and a café-au-lait macule, we identified an ~15 kb 16q24.1 duplication inherited from the reportedly healthy father, in addition to a ~1.09 Mb mosaic 17q11.2 deletion. In a 13-year-old patient with autism and mood disorder, we found an ~0.3 Mb duplication harboring and an ~0.5 Mb 16q23.3 duplication, both inherited from the father with bipolar disorder. In a 47-year old patient with pyloric stenosis, mesenterium commune, and aplasia of the appendix, we identified an ~0.4 Mb duplication in 16q24.1 encompassing 16 genes including . The patient transmitted the duplication to her daughter, who presented with similar symptoms. In a fourth patient with speech and motor delay, and borderline intellectual disability, we identified an ~1.7 Mb duplication adjacent to a large minisatellite. This duplication has a complex structure and arose on the maternal chromosome, likely as a result of a DNA replication error initiated by the adjacent large tandem repeat. Using bioinformatic and array CGH analyses of the minisatellite, we found a large variation of its size in several different species and individuals, demonstrating both its evolutionarily instability and population polymorphism. Conclusions: Our data indicate that constitutional duplication of in humans is not associated with any pediatric lung abnormalities. We propose that patients with gut malrotation, pyloric or duodenal stenosis, and gall bladder agenesis should be tested for alterations. We suggest that instability of minisatellites greater than 1 kb can lead to structural variation due to DNA replication errors. © Dharmadhikari et al.; licensee BioMed Central.