Deletions of Xp Provide Evidence for the Role of Holocytochrome C-Type Synthase (HCCS) in Congenital Diaphragmatic Hernia

Baylor College of Medicine, Houston, Texas, USA.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 06/2010; 152A(6):1588-90. DOI: 10.1002/ajmg.a.33410
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Available from: Sau Wai Cheung, Sep 28, 2015
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    • "The majority of patients had a chromosomal abnormality resulting in monosomy for the Xp22.2 region. MLS syndrome mainly affects females, however, ten males with an XX karyotype and Y-chromosomal material or 46,XY and a mosaic inversion involving the band Xp22.2 are known [11,15,29,32-36]. Finally, HCCS turned out to be the culprit gene in Xp22.2 [4] and is implicated in all chromosomal rearrangements reported in MLS syndrome-affected individuals to date. "
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    ABSTRACT: Segmental Xp22.2 monosomy or a heterozygous HCCS mutation is associated with the microphthalmia with linear skin defects (MLS) or MIDAS (microphthalmia, dermal aplasia, and sclerocornea) syndrome, an X-linked disorder with male lethality. HCCS encodes the holocytochrome c-type synthase involved in mitochondrial oxidative phosphorylation (OXPHOS) and programmed cell death. We characterized the X-chromosomal abnormality encompassing HCCS or an intragenic mutation in this gene in six new female patients with an MLS phenotype by cytogenetic analysis, fluorescence in situ hybridization, sequencing, and quantitative real-time PCR. The X chromosome inactivation (XCI) pattern was determined and clinical data of the patients were reviewed. Two terminal Xp deletions of >=11.2 Mb, two submicroscopic copy number losses, one of ~850 kb and one of >=3 Mb, all covering HCCS, 1 nonsense, and one mosaic 2-bp deletion in HCCS are reported. All females had a completely (>98:2) or slightly skewed (82:18) XCI pattern. The most consistent clinical features were microphthalmia/anophthalmia and sclerocornea/corneal opacity in all patients and congenital linear skin defects in 4/6. Additional manifestations included various ocular anomalies, cardiac defects, brain imaging abnormalities, microcephaly, postnatal growth retardation, and facial dysmorphism. However, no obvious clinical sign was observed in three female carriers who were relatives of one patient. Our findings showed a wide phenotypic spectrum ranging from asymptomatic females with an HCCS mutation to patients with a neonatal lethal MLS form. Somatic mosaicism and the different ability of embryonic cells to cope with an OXPHOS defect and/or enhanced cell death upon HCCS deficiency likely underlie the great variability in phenotypes.
    Orphanet Journal of Rare Diseases 04/2014; 9(1):53. DOI:10.1186/1750-1172-9-53 · 3.36 Impact Factor
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    ABSTRACT: Microphthalmia with linear skin defects syndrome (MLS or MIDAS, OMIM #309801) is a rare X-linked male-lethal disorder characterized by microphthalmia or other ocular anomalies and skin lesions limited to the face and neck. However, inter- and intrafamilial variability is high. Here we report a familial case of MLS. A mother and daughter with MLS underwent a complete ophthalmological examination, and extensive imaging, including anterior segment pictures, corneal topography and keratometry, autofluorescence, infrared reflectance and red free images, as well as spectral-domain optical coherence tomography. The mother also underwent full-field flash electroretinography. In addition, high-resolution array comparative genomic hybridization analysis was performed in both as well as in the maternal grandparents of the proband. Microphthalmia and retinal abnormalities were noted in the proband and the mother, whereas only the mother presented with scars of the typical neonatal linear skin defects. Array comparative genomic hybridization analysis revealed a 185-220 kb deletion on chromosome band Xp22.2 including the entire HCCS gene. The identification of a deletion including HCCS led to the diagnosis of MLS in these patients. Retinal abnormalities can be part of the ocular manifestations of MLS.
    Molecular vision 02/2013; 19:311-8. · 1.99 Impact Factor
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    ABSTRACT: Congenital diaphragmatic hernia (CDH) is a common birth defect with a high mortality and morbidity. Although numerous chromosomal aberrations and gene mutations have been associated with CDH, the etiology of the diaphragmatic defect is identified in less than 50% of patients. This review discusses the some of the more frequent, recurrent karyotypic abnormalities in which CDH is a feature, including 15q26, 8p23.1 and 4p16.3 deletions and tetrasomy 12p (Pallister–Killian syndrome), together with some of the syndromes in which CDH is a relatively common feature, including Fryns syndrome, Matthew-Wood syndrome, overgrowth syndromes and Donnai–Barrow syndrome. In the era of genomic technologies, our knowledge of the genes and chromosome regions involved in pathogenesis of CDH is likely to advance significantly.
    European Journal of Medical Genetics 08/2014; 57(8). DOI:10.1016/j.ejmg.2014.04.012 · 1.47 Impact Factor
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