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

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.

Characterization of a new X-linked mental retardation syndrome with microcephaly, cortical malformation, and thin habitus.

X-linked mental retardation (XLMR) affects 1-2/1,000 males and accounts for approximately 10% of all mental retardation (MR). We have ascertained a syndromic form of XLMR segregating within a five-generation family with seven affected males. Prominent characteristics include mild to severe MR, cortical malformation, microcephaly, seizures, thin build with distinct facial features including a long and thin face, epicanthic folds, almond-shaped eyes, upslanting palpebral fissures and micrognathia and behavioral problems. Carrier females have normal physical appearance and intelligence. This combination of features is unreported and distinct from Lujan-Fryns syndrome, Snyder-Robinson syndrome, and zinc finger DHHC domain-containing 9-associated MR. We propose the name of this new syndrome to be CK syndrome.

1.6Mb deletion in chromosome band 3q29 associated with eye abnormalities.

We report on a patient with a de novo microdeletion 3q29 detected by molecular karyotyping using array CGH analysis. The girl displayed microphthalmia and cataract, hyperplastic pyloric stenosis, mild dysmorphic facial features, and developmental delay. Array CGH analysis uncovered a 1.6Mb deletion within chromosome band 3q29, which overlaps with the commonly deleted region in 3q29 microdeletion syndrome. According to published data, none of the patients with deletion 3q29 showed either congenital cataract and microphthalmia, or other ocular features. Our report expands the phenotypic spectrum of the 3q29 microdeletion syndrome by adding structural eye malformations.

Chromosomal map of human brain malformations.

The etiology of most central nervous system (CNS) malformations remains unknown. We have utilized the fact that autosomal chromosome aberrations are commonly associated with CNS malformations to identify new causative gene loci. The human cytogenetic database, a computerized catalog of the clinical phenotypes associated with cytogenetically detectable human chromosome aberrations, was used to identify patients with 14 selected brain malformations including 541 with deletions, and 290 carrying duplications. These cases were used to develop an autosomal deletion and duplication map consisting of 67 different deleted malformation associated bands (MABs) in 55 regions and 88 different duplicated MABs in 36 regions; 31 of the deleted and 8 duplicated MABs were highly significantly associated (P < 0.001). All holoprosencephaly MABs found in the database contained a known HPE gene providing some level of validation for the approach. Significantly associated MABs are discussed for each malformation together with the published data about known disease-causing genes and reported malformation-associated loci, as well as the limitations of the proposed approach.

Duplication of (12)(pter-q13.3) combined with deletion of (22)(pter-q11.2) in a patient with features of both chromosome aberrations.

We report a patient with multiple dysmorphic signs and congenital malformations, representing a combination of clinical features of duplication (12p) and deletion (22)(q11.2) syndromes. The girl had overgrowth at birth, showed abnormal cranio-facial findings, cleft uvula, a complex conotruncal heart defect, a polycystic right kidney, and an umbilical hernia. She died at the age of 6 months of cardio-respiratory failure. Cytogenetic examination demonstrated a derivative chromosome 12 replacing one of the two chromosomes 22. The paternal karyotype was normal 46,XY while the mother's karyotype was 46,XX,rcp(12;22)(q13.2;q11.2). According to the published data, all patients with deletion 22q11.2 combined with other unbalanced chromosomal aberration have a more severe clinical expression than those with interstitial deletions.