Novel mutations including deletions of the entire OFD1 gene in 30 families with type 1 orofaciodigital syndrome: a study of the extensive clinical variability

Abstract

OFD1, now recognized as a ciliopathy, is characterized by malformations of the face, oral cavity and digits, and is transmitted as an X-linked condition with lethality in males. Mutations in OFD1 also cause X-linked Joubert syndrome (JBTS10) and Simpson-Golabi-Behmel syndrome type 2 (SGBS2). We have studied 55 sporadic and six familial cases of suspected OFD1. Comprehensive mutation analysis in OFD1 revealed mutations in 37 female patients from 30 families; 22 mutations have not been previously described including two heterozygous deletions spanning OFD1 and neighbouring genes. Analysis of clinical findings in patients with mutations revealed that oral features are the most reliable diagnostic criteria. A first, detailed evaluation of brain MRIs from seven patients with cognitive defects illustrated extensive variability with the complete brain phenotype consisting of complete agenesis of the corpus callosum, large single or multiple interhemispheric cysts, striking cortical infolding of gyri, ventriculomegaly, mild molar tooth malformation and moderate to severe cerebellar vermis hypoplasia. Although the OFD1 gene apparently escapes X-inactivation, skewed inactivation was observed in seven of 14 patients. The direction of skewing did not correlate with disease severity, reinforcing the hypothesis that additional factors contribute to the extensive intrafamilial variability.

Figure 1

Mother–daughter pairs showing some of the typical clinical findings in OFD1. The pedigree symbols for the family members refer to the pedigrees shown in Fig. 3. A–E Family 1: the mother (II-2, A) and her youngest, more severely affected daughter (III-2, B–E); F–L Family 6: mother (I-1, F, J) and her daughter (II-1, G–I, K–L); M, N Family 9: mother and daughter, O–S Family 10: mother (I-1, O and Q) and daughter (II-2, P–S). T–Z: The only affected individual in family 29, in whom the entire OFD1 gene is deleted on one allele. Typical facial features include frontal bossing (G, M, N, T), a broad nasal ridge (G, N, T), downslanting palpebral fissures (A, F, N, T), facial asymmetry (A, B, F, G, O), and midface hypoplasia (B, G, T). Typical oral features shown include cleft lip and bifid tongue (C, I, P), tongue hamartomas (C, I, X). Skeletal features include polydactyly (surgically corrected in E), brachydactyly (J, K, R, Y), clinodactyly (J, K, Q), and syndactyly (J, K). Alopecia is shown in patient 29 in U and V.

Figure 2

Brain MRIs of patients with OFD1 mutations. A, B: Patient II-1 in family 1, showing mild asymmetry with the right frontal lobe smaller than the left (A, B), reduced white matter volume, and mildly enlarged lateral ventricle (A). C, D: Patient 28 showing a short, thin, and dysmorphic corpus callosum. E–H and L: Patient II-2 in family 10, showing a large interhemispheric cyst (F), I–K: Patient 14, showing reduced white matter volume (I), mildly enlarged and widely separated lateral ventricles (I), severe partial agenesis of the corpus callosum (K), and possibly subtle cerebellar hypoplasia (K). M–P: Patient 12, showing a prominent bossed forehead (N, O), numerous large perivascular (Virchow–Robin) spaces in the white matter (mostly posteriorly) (N and P), a short, thin corpus callosum, and mild cerebellar vermis hypoplasia (O). Q–T: Patient 26, showing multiple, large interhemispheric cysts displacing the right hemisphere laterally (Q–S), reduced white matter volume (Q, R), a markedly enlarged third ventricle with an uncertain connection to the interhemispheric cysts (Q, R), and complete agenesis of the corpus callosum (Q, S). U–X: Patient II-1 in family 27, showing a large interhemispheric cyst displacing both hemispheres laterally (U–W), reduced white matter volume, particularly frontally (U, V), a markedly enlarged third ventricle that appears to connect to the interhemispheric cysts (V, W), complete agenesis of the corpus callosum (W), mildly small cerebellum with abnormally small anterior vermis, and mildly small posterior fossa (W).

Figure 3

The analysis of possible X-inactivation in familial cases of OFD1 and two patients with deletion of the entire gene. A: Family 1; B: Family 6; C: Family 10; D: Family 19; and E: Family 27. F: Patients 29 and 30 with deletion of OFD1, and the results of the assay in DNA from a healthy male used as a control. Alleles of the CAG repeat in the androgen receptor gene, AR, on Xq22 are shown before (HhaI-) and after (HhaI+) restriction enzyme digestion, and the affection status of the individuals tested is show on the pedigrees. The sizes of the alleles are shown in bp, and the allele carrying the OFD1 mutation is labelled red, bold, and underlined, when it was possible, via haplotyping, to track the mutant allele in the family. The segregation of the AR alleles in family 24 was not informative, so that the mutation allele could not be identified.