Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis.

Ellis-van Creveld syndrome (EvC, MIM 225500) is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly and dysplastic nails and teeth. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals. The disease was mapped to chromosome 4p16 in nine Amish subpedigrees and single pedigrees from Mexico, Ecuador and Brazil. Weyers acrodental dysostosis (MIM 193530), an autosomal dominant disorder with a similar but milder phenotype, has been mapped in a single pedigree to an area including the EvC critical region. We have identified a new gene (EVC), encoding a 992-amino-acid protein, that is mutated in individuals with EvC. We identified a splice-donor change in an Amish pedigree and six truncating mutations and a single amino acid deletion in seven pedigrees. The heterozygous carriers of these mutations did not manifest features of EvC. We found two heterozygous missense mutations associated with a phenotype, one in a man with Weyers acrodental dysostosis and another in a father and his daughter, who both have the heart defect characteristic of EvC and polydactyly, but not short stature. We suggest that EvC and Weyers acrodental dysostosis are allelic conditions.

Congenital heart diseases in children with Noonan syndrome: An expanded cardiac spectrum with high prevalence of atrioventricular canal.

OBJECTIVE: To report the relative prevalence of various forms of congenital heart disease (CHD) in children with Noonan syndrome (NS) and to describe anatomic characteristics of the subgroup of patients with atrioventricular canal (AVC). STUDY DESIGN: Phenotypic and cardiologic examinations were performed in 136 patients with NS and CHD evaluated at our hospital from January 1986 to December 1998. Cardiac evaluation included chest x-ray film, electrocardiogram, 2-dimensional and color Doppler echocardiography, cardiac catheterization with angiocardiography, and cardiac surgery. RESULTS: The CHDs classically reported in NS, including pulmonary stenosis (39%), hypertrophic cardiomyopathy (10%), atrial septal defect (8%), and tetralogy of Fallot (4%), are well represented in our series; however, aortic coarctation (9%) and anomalies of the mitral valve (6%) may also occur in this syndrome. Moreover, AVC was diagnosed in 21 patients, representing 15% of all CHDs in our series. All patients showed a partial form of AVC, and an associated subaortic stenosis caused by additional anomalies of the mitral valve was detected in 5 of 21 (23.8%) of those patients. CONCLUSION: Left-sided lesions, such as aortic coarctation and anomalies of the mitral valve, are not rare in patients with NS and CHD. Moreover, in this syndrome AVC is quite frequent, the partial form is prevalent, and subaortic stenosis caused by additional anomalies of the mitral valve may be present. This information should be taken into consideration during the cardiologic evaluation of children with NS.

Localization of a gene for familial patella aplasia-hypoplasia (PTLAH) to chromosome 17q21-22.

Patella aplasia-hypoplasia (PTLAH) is a rare genetic defect characterized by congenital absence or marked reduction of the patella. PTLAH can occur either as an isolated defect or in association with other malformations, and it characteristically occurs in the nail-patella syndrome and in some chromosome imbalances. We report the first evidence of linkage for isolated PTLAH in an extended Venezuelan family. After exclusion of the candidate chromosome regions where disorders associated with PTLAH have been mapped, a genomewide scan was performed that supported mapping of the disease locus within a region of 12 cM on chromosome 17q22. Two marker loci (D17S787 and D17S1604) typed from this region gave maximum LOD scores >3. Accordingly, multipoint analysis gave a maximum LOD score of 3.39, with a most likely location for the disease gene between D17S787 and D17S1604. Sequencing of the noggin gene, a candidate mapping between these markers, failed to reveal any mutation in affected subjects.