Cerebro-oculo-facio-skeletal syndrome with a nucleotide excision-repair defect and a mutated XPD gene, with prenatal diagnosis in a triplet pregnancy

Cerebro-oculo-facio-skeletal (COFS) syndrome is a recessively inherited rap idly progressive neurologic disorder leading to brain atrophy, with calcifi cations, cataracts, microcornea, optic atrophy, progressive joint contractu res, and growth failure. Cockayne syndrome (CS) is a recessively inherited neurodegenerative disorder characterized by low to normal birth weight, gro wth failure, brain dysmyelination with calcium deposits, cutaneous photosen sitivity, pigmentary retinopathy and/or cataracts, and sensorineural hearin g loss. Cultured CS cells are hypersensitive to UV radiation, because of im paired nucleotide-excision repair (NER) of UV-induced damage in actively tr anscribed DNA, whereas global genome NER is unaffected. The abnormalities i n 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 conc urrently have clinical features of another NER syndrome, xeroderma pigmento sum (XP). Clinically observed similarities between COFS syndrome and CS hav e been followed by discoveries of cases of COFS syndrome that are associate d with mutations in the XPG and CSB genes. Here we report the first involve ment of the XPD gene in a new case of UV-sensitive COFS syndrome, with hete rozygous substitutions-a R616W null mutation (previously seen in patients i n XP complementation group D) and a unique D681N mutation-demonstrating tha t a third gene can be involved in COFS syndrome. We propose that COFS syndr ome be included within the already known spectrum of NER disorders: XP, CS, and trichothiodystrophy. We predict that future patients with COFS syndrom e 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 singleto n pregnancies at risk for COFS syndrome. This result strongly underlines th e need for screening of patients with COFS syndrome, for either UV sensitiv ity or DNA-repair abnormalities.