Cerebro-Oculo-Facio-Skeletal Syndrome with a Nucleotide Excision–Repair Defect and a Mutated XPD Gene, with Prenatal Diagnosis in a Triplet Pregnancy

Abstract

Cerebro-oculo-facio-skeletal (COFS) syndrome is a recessively inherited rapidly progressive neurologic disorder leading to brain atrophy, with calcifications, cataracts, microcornea, optic atrophy, progressive joint contractures, and growth failure. Cockayne syndrome (CS) is a recessively inherited neurodegenerative disorder characterized by low to normal birth weight, growth failure, brain dysmyelination with calcium deposits, cutaneous photosensitivity, pigmentary retinopathy and/or cataracts, and sensorineural hearing loss. Cultured CS cells are hypersensitive to UV radiation, because of impaired nucleotide-excision repair (NER) of UV-induced damage in actively transcribed DNA, whereas global genome NER is unaffected. The abnormalities in CS are caused by mutated CSA or CSB genes. Another class of patients with CS symptoms have mutations in the XPB, XPD, or XPG genes, which result in UV hypersensitivity as well as defective global NER; such patients may concurrently have clinical features of another NER syndrome, xeroderma pigmentosum (XP). Clinically observed similarities between COFS syndrome and CS have been followed by discoveries of cases of COFS syndrome that are associated with mutations in the XPG and CSB genes. Here we report the first involvement of the XPD gene in a new case of UV-sensitive COFS syndrome, with heterozygous substitutions-a R616W null mutation (previously seen in patients in XP complementation group D) and a unique D681N mutation-demonstrating that a third gene can be involved in COFS syndrome. We propose that COFS syndrome be included within the already known spectrum of NER disorders: XP, CS, and trichothiodystrophy. We predict that future patients with COFS syndrome will be found to have mutations in the CSA or XPB genes, and we document successful use of DNA repair for prenatal diagnosis in triplet and singleton pregnancies at risk for COFS syndrome. This result strongly underlines the need for screening of patients with COFS syndrome, for either UV sensitivity or DNA-repair abnormalities.

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

“…The similar neuropathologies in COFS, CS, and AGS have been noted previously by others [19,70]. COFS can also result from mutations in XPD [71], XPG [72], or ERCC1 [73], but neuropathological information on these cases is limited.…”

Mammalian Transcription-Coupled Excision Repair

“…CS and COFS can thus be considered as two syndromes with a common pathogenesis, and it has been suggested in several studies that both actually represent the two borders of a clinical spectrum caused by the same biochemical defect (Laugel et al 2008). As well as COFS patients with a CSB mutation, patients originally diagnosed as COFS but with mutations in the core NER genes XPD (Graham et al 2001), XPG (Hamel et al 1996;Nouspikel et al 1997), and ERCC1 (Jaspers et al 2007) have been identified. These latter patients with mutations in the core NER genes represent the most severe cases, likely because both TC-NER and GG-NER are affected.…”

A new, tenth subunit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A

“…Photosensitive features of xeroderma pigmentosum are caused by defective NER, whereas features of Cockayne syndrome and TTD are attributed to defective TCR and transcription function. Most individuals with these syndromes associated with TFIIH carry mutations of XPD or, in a few cases, of XPB, the two TFIIH helicase subunits [9][10][11][12] . A third, unidentified gene that causes photosensitive TTD 13,14 , called GTF2H5, also shows association with TFIIH 1 .…”