These authors contributed equally to this work.
Exome sequencing in a family with an X-linked lethal malformation syndrome: clinical consequences of hemizygous truncating OFD1 mutations in male patients
Article first published online: 1 MAY 2012
© 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd
Volume 83, Issue 2, pages 135–144, February 2013
How to Cite
Tsurusaki, Y., Kosho, T., Hatasaki, K., Narumi, Y., Wakui, K., Fukushima, Y., Doi, H., Saitsu, H., Miyake, N. and Matsumoto, N. (2013), Exome sequencing in a family with an X-linked lethal malformation syndrome: clinical consequences of hemizygous truncating OFD1 mutations in male patients. Clinical Genetics, 83: 135–144. doi: 10.1111/j.1399-0004.2012.01885.x
- Issue published online: 7 JAN 2013
- Article first published online: 1 MAY 2012
- Accepted manuscript online: 30 MAR 2012 11:44AM EST
- Received 14 January 2012, revised and accepted for publication 26 March 2012
- exome sequencing;
- OFD1 gene;
- splicing mutation;
- X-linked congenital malformation syndrome
Tsurusaki Y, Kosho T, Hatasaki K, Narumi Y, Wakui K, Fukushima Y, Doi H, Saitsu H, Miyake N, Matsumoto N. Exome sequencing in a family with an X-linked lethal malformation syndrome: clinical consequences of hemizygous truncating OFD1 mutations in male patients.
Oral-facial-digital syndrome type 1 (OFD1; OMIM #311200) is an X-linked dominant disorder, caused by heterozygous mutations in the OFD1 gene and characterized by facial anomalies, abnormalities in oral tissues, digits, brain, and kidney; and male lethality in the first or second trimester pregnancy. We encountered a family with three affected male neonates having an ‘unclassified’ X-linked lethal congenital malformation syndrome. Exome sequencing of entire transcripts of the whole X chromosome has identified a novel splicing mutation (c.2388+1G > C) in intron 17 of OFD1, resulting in a premature stop codon at amino acid position 796. The affected males manifested severe multisystem complications in addition to the cardinal features of OFD1 and the carrier female showed only subtle features of OFD1. The present patients and the previously reported male patients from four families (clinical OFD1; Simpson-Golabi-Behmel syndrome, type 2 with an OFD1 mutation; Joubert syndrome-10 with OFD1 mutations) would belong to a single syndrome spectrum caused by truncating OFD1 mutations, presenting with craniofacial features (macrocephaly, depressed or broad nasal bridge, and lip abnormalities), postaxial polydactyly, respiratory insufficiency with recurrent respiratory tract infections in survivors, severe mental or developmental retardation, and brain malformations (hypoplasia or agenesis of corpus callosum and/or cerebellar vermis and posterior fossa abnormalities).