American journal of medical genetics. Part A
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Am. J. Med. Genet. A · Aug 2014
The spectrum of ZEB2 mutations causing the Mowat-Wilson syndrome in Japanese populations.
Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by moderate or severe intellectual disability, a characteristic facial appearance, microcephaly, epilepsy, agenesis or hypoplasia of the corpus callosum, congenital heart defects, Hirschsprung disease, and urogenital/renal anomalies. It is caused by de novo heterozygous loss of function mutations including nonsense mutations, frameshift mutations, and deletions in ZEB2 at 2q22. ZEB2 encodes the zinc finger E-box binding homeobox 2 protein consisting of 1,214 amino acids. ⋯ A transfection study demonstrated that the cellular level of the longest form of the mutant ZEB2 protein harboring the p. D1204Rfs*29 mutation was remarkably low. The results showed that the 3'-end frameshift mutation of ZEB2 causes MWS due to ZEB2 instability.
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Am. J. Med. Genet. A · Aug 2014
Case ReportsTwo deletions overlapping a distant FOXF1 enhancer unravel the role of lncRNA LINC01081 in etiology of alveolar capillary dysplasia with misalignment of pulmonary veins.
Position effects due to disruption of distant cis-regulatory regions have been reported for over 40 human gene loci; however, the underlying mechanisms of long-range gene regulation remain largely unknown. We report on two patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) caused by overlapping genomic deletions that included a distant FOXF1 transcriptional enhancer mapping 0.3 Mb upstream to FOXF1 on 16q24.1. ⋯ Both deletions arose de novo on maternal copy of the chromosome 16, supporting the notion that FOXF1 is paternally imprinted in the human lungs. RNAi-mediated knock-down of LINC01081 in normal fetal lung fibroblasts showed that this lncRNA positively regulates FOXF1 transcript level, further indicating that decrease in LINC01081 expression can contribute to development of ACDMPV.
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Am. J. Med. Genet. A · Aug 2014
Intragenic rearrangements in X-linked intellectual deficiency: results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes.
High-resolution array comparative genomic hybridization (a-CGH) enables the detection of intragenic rearrangements, such as single exon deletion or duplication. This approach can lead to the identification of new disease genes. We report on the analysis of 54 male patients presenting with intellectual deficiency (ID) and a family history suggesting X-linked (XL) inheritance or maternal skewed X-chromosome inactivation (XCI), using a home-made X-chromosome-specific microarray covering the whole human X-chromosome at high resolution. ⋯ The first CNV is a deletion of the first exon of the TRPC5 gene, encoding a cation channel implicated in dendrite growth and patterning, in a child presenting with ID and an autism spectrum disorder (ASD). The second CNV is a partial deletion of KLHL15, in a patient with severe ID, epilepsy, and anomalies of cortical development. In both cases, in spite of strong arguments for clinical relevance, we were not able at this stage to confirm pathogenicity of the mutations, and the causality of the variants identified in XLID remains to be confirmed.
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Am. J. Med. Genet. A · Aug 2014
Fatigue in adults with Marfan syndrome, occurrence and associations to pain and other factors.
This study aims to investigate how fatigue affects adults with verified Marfan syndrome (MFS) in their daily lives, by examining fatigue levels and prevalence of severe fatigue compared to the general Norwegian population and individuals with other comparable chronic conditions. We investigated associations between socio-demographic characteristics, Marfan-related health problems, pain and fatigue. A cross-sectional study was conducted, using a postal questionnaire including the Fatigue Severity Scale (FSS) and questions on socio-demographic characteristics, Marfan-related health problems and pain. ⋯ Chronic pain and employment status show significant associations to fatigue. This implies that fatigue is important to address when meeting MFS patients in clinical practice. There is need for more research on fatigue in Marfan syndrome.
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Am. J. Med. Genet. A · Aug 2014
Phenotypic features in patients with 15q11.2(BP1-BP2) deletion: further delineation of an emerging syndrome.
15q11.2 deletions flanked by BP1 and BP2 of the Prader-Willi/Angelman syndrome region have recently been linked to a range of neurodevelopment disorders including intellectual disability, speech and language delay, motor delay, autism spectrum disorders, epilepsy, and schizophrenia. Array CGH analysis of 14,605 patients referred for diagnostic cytogenetic testing found that 83 patients (0.57%) carried the 15q11.2(BP1-BP2) deletion. ⋯ Notably, motor delay was significantly more common (OR = 6.37). These data indicate that developmental delay, motor delay, and speech and language delay are common clinical features associated with this deletion, providing substantial evidence to support this CNV as a susceptibility locus for a spectrum of neurodevelopmental disorders. © 2014 Wiley Periodicals, Inc.