A synonymous mutation in TCOF1 causes Treacher Collins syndrome due to mis-splicing of a constitutive exon.

Interpretation of the pathogenicity of sequence alterations in disease-associated genes is challenging. This is especially true for novel alterations that lack obvious functional consequences. We report here on a patient with Treacher Collins syndrome (TCS) found to carry a previously reported mutation, c.122C > T, which predicts p.A41V, and a novel synonymous mutation, c.3612A > C. Pedigree analysis showed that the c.122C > T mutation segregated with normal phenotypes in multiple family members while the c.3612A > C was de novo in the patient. Analysis of TCOF1 RNA in lymphocytes showed a transcript missing exon 22. These results show that TCS in the patient is due to haploinsufficiency of TCOF1 caused by the synonymous de novo c.3612A > C mutation. This study highlights the importance of clinical and pedigree evaluation in the interpretation of known and novel sequence alterations.

Association between homeobox-containing gene MSX1 and the occurrence of limb deficiency.

Animal studies have suggested an important role for the homeobox-containing gene MSX1 in limb, oralfacial, and cardiac malformations. In this study of 516 Caucasians with isolated birth defects registered in the Maryland Birth Defects Reporting and Information System (BDRIS), we report an association between a dinucleotide repeat polymorphism in MSX1 and isolated limb deficiency. Frequencies of rare alleles at the MSX1 locus are significantly higher among 34 infants with limb deficiency compared to 482 infants with other isolated birth defects (oral clefts, dislocation of hip, clubfoot, hypospadias, polydactyly, or syndactyly) (chi2 = 11.0, df = 3, P = 0.012). Infants carrying the rare alleles had a 4.81-fold higher risk of a limb deficiency when the mother reported smoking during pregnancy, compared to infants who are homozygous for the common allele and whose mother did not smoke. The significance of this apparent gene-environment interaction is attributed to infants with malformation of the lower limb. The statistical association and potential gene-environment interaction observed in this study (which was originally designed to investigate oral clefts) are compatible with results from animal studies involving the MSX1 gene, and suggests that further investigation into biological mechanisms is warranted.

Achondroplasia is defined by recurrent G380R mutations of FGFR3.

Genomic DNA from 154 unrelated individuals with achondroplasia was evaluated for mutations in the fibroblast growth factor receptor 3 (FGFR3) transmembrane domain. All but one, an atypical case, were found to have a glycine-to-arginine substitution at codon 380. Of these, 150 had a G-to-A transition at nt 1138, and 3 had a G-to-C transversion at this same position. On the basis of estimates of the prevalence of achondroplasia, the mutation rate at the FGFR3 1138 guanosine nucleotide is two to three orders of magnitude higher than that previously reported for tranversions and transitions in CpG dinucleotides. To date, this represents the most mutable single nucleotide reported in the human genome. The homogeneity of mutations in achondroplasia is unprecedented for an autosomal dominant disorder and may explain the relative lack of heterogeneity in the achondroplasia phenotype.

Localization of the achondroplasia gene to the distal 2.5 Mb of human chromosome 4p.

Achondroplasia has been mapped to 4p16.3 using 18 multigenerational families with achondroplasia and 10 short tandem repeat polymorphic markers from this region. No evidence of genetic heterogeneity was found. Analysis of a recombinant family localizes the achondroplasia locus to the 2.5 Mb region between D4S43 and the telomere. Multipoint linkage analysis favors placement telomeric of D4S412. The establishment of closely linked markers will facilitate positional cloning of the achondroplasia gene and permit prenatal diagnosis of homozygous achondroplasia for at risk couples.

A type X collagen mutation causes Schmid metaphyseal chondrodysplasia.

The expression of type X collagen is restricted to hypertrophic chondrocytes in regions undergoing endochondral ossification, such as growth plates. The precise function of type X collagen is unknown but the tissue-specific expression prompted us to examine the gene in hereditary disorders of cartilage and bone growth (osteochondrodysplasias). We have identified a 13 base pair deletion in one type X collagen allele segregating with autosomal dominant Schmid metaphyseal chondrodysplasia in a large Mormon kindred (lod score = 18.2 at theta = 0). The mutation produces a frameshift which alters the highly conserved C-terminal domain of the alpha 1(X) chain and reduces the length of the polypeptide by nine residues. This mutation may prevent association of the mutant polypeptide during trimer formation, resulting in a decreased amount of normal protein.