Exome sequencing in a family with an X‐linked lethal malformation syndrome: clinical consequences of hemizygous truncating OFD1 mutations in male patients

Abstract

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).

Oral‐facial‐digital syndrome type 1 in males: Congenital heart defects are included in its phenotypic spectrum

“…CHDs are commonly observed in many ciliopathy syndromes including different types of OFD syndromes (33–100%) (Digilio et al, 1999; Karp et al, 2012). The male fetus with OFD1 described in this report had a HLHS which can be classified as “left‐sided obstruction defect”: HLHS was also present in a male patients with OFD1 described previously (Tsurusaki et al, 2013). In three other male patients with OFD1 ASD and AVSD were described (Goodship et al, 1991; Tsurusaki et al, 2013).…”

“…The male fetus with OFD1 described in this report had a HLHS which can be classified as “left‐sided obstruction defect”: HLHS was also present in a male patients with OFD1 described previously (Tsurusaki et al, 2013). In three other male patients with OFD1 ASD and AVSD were described (Goodship et al, 1991; Tsurusaki et al, 2013). Several reports of patients with other OFD syndromes describe patients with left‐sided cardiac obstructions, some of them in combination with AVSD (Balci, Onol, Eryilmaz, & Haytoglu, 1997; Digilio, Marino, Giannotti, & Dallapiccola, 1996; Gustavson, Kreuger, & Petersson, 1971; Iaccarino, Lonardo, Giugliano, & Della Bruna, 1985; Nevin & Thomas, 1989; Orstavik, Lindemann, Solberg, Foerster, & Sørland, 1992; Saari, Lovell, Yu, & Bellus, 2015; Váradi, Szabó, & Papp 1980).…”

“…A hemizygous pathogenic mutation in OFD1 (c.2101C>T; p.(Gln701*)) was demonstrated by exome sequencing in the proband. Only five live born male patients with OFD1 have been previously reported in the literature (Table 1) (Goodship et al, 1991; Tsurusaki et al, 2013). Four of the five patients had CHDs (ASD, AVSD, HLHS).…”

“…To date, only five liveborn male patients have been reported in the literature. Interestingly, in four of them CHDs were described: atrial septal defect (ASD), atrioventricular septal defect (AVSD), and hypoplastic left heart syndrome (HLHS) (Table 1) (Gillerot, Heimann, Fourneau, Verellen‐Dumoulin, & Van Maldergem, 1993; Goodship, Platt, Smith, & Burn, 1991; Tsurusaki et al, 2013). All died within the first 14 days of life.…”

Next-generation sequencing: impact of exome sequencing in characterizing Mendelian disorders

“…In an example, exome sequencing of entire three affected males having an unclassified X-linked lethal congenital malformation syndrome identified a splicing mutation in OFD1 gene. 51 …”