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: 2.3). 01/2010; 152A(6):1588-90. DOI: 10.1002/ajmg.a.33410
Source: PubMed
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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.
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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.
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    ABSTRACT: IntroductionTrisomy X (47,XXX) is a human sex chromosome aneuploidy in which females have an extra X chromosome, compared to the 46,XX karyotype in typical females. Females with 47,XXX karyotypes have been reported to have varied phenotypic changes that include features like tall stature, epicanthal folds, hypotonia and clinodactyly. Seizures, renal and genitourinary abnormalities, and premature ovarian failure are also few associated findings. However, puberty, sexual development and fertility are usually normal in trisomy X females (Tartaglia et al.2010). The case presented in this study had two consecutive spontaneous pregnancy losses though she was devoid of any intrauterine malformation as revealed by her ultrasonography report. Her immunological profile was absolutely normal. Apparently, the female was not having any kind of facial deformity or syndromic features. Cytogenetic evaluation of the female revealed 47(XXX) karyotype with del(Xp21 →Xpter) which was possibly the only dis ...
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