Mutations in CDMP1 cause autosomal dominant brachydactyly type C.
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Base Sequence↗
Biomedical subjects
W Reardon
Publications and source records attributed to W Reardon.
Elastin: genomic structure and point mutations in patients with supravalvular aortic stenosis.
We describe the complete exon-intron structure of the human elastin (ELN) gene located at chromosome 7q11.23. There are 34 exons occupying approximately 47 kb of genomic DNA. All exons are in-frame, allowing exon skipping without disrupting the reading frame. Microsatellites are located in introns 17 and 18. Deletions of all or large parts of the ELN gene have been previously reported in two patients with supravalvular aortic stenosis (SVAS), and SVAS is also a frequent feature of Williams syndrome, where patients are hemizygous for ELN. We list primer pairs for amplifying each exon, with flanking intron, from genomic DNA to allow detection of point mutations in the ELN gene. We show that some patients with isolated SVAS have point mutations that are predicted to lead to premature chain termination. Knowledge of the genomic structure will allow more extensive mutation screening in genomic DNA of patients with SVAS and other conditions.
Amino Acid Sequence↗
The TWIST gene, although not disrupted in Saethre-Chotzen patients with apparently balanced translocations of 7p21, is mutated in familial and sporadic cases.
The TWIST gene maps to 7p21 and mutations in the gene have been reported in the Saethre-Chotzen form of craniosynostosis. The position of the Saethre-Chotzen gene has previously been refined by FISH analysis of four patients carrying balanced translocations involving 7p21 which suggested that it was located between D7S488 and D7S503. We report here that the breakpoints in four translocation patients do not interrupt the coding sequence of the TWIST gene and thus most likely act through a positional effect. Twelve Saethre-Chotzen cases were found to have TWIST mutations. Four of these families had been used as part of the linkage study of the Saethre-Chotzen locus. The mutations detected included missense and nonsense mutations and three cases of a 21 bp duplication. Although phenotypically diagnosed as having Saethre-Chotzen syndrome, three families were found to have a pro250arg mutation of FGFR3.
Acrocephalosyndactylia↗
Pendred syndrome--100 years of underascertainment?
Pendred syndrome is an autosomal recessive condition classically characterized by deafness and goitre. Since both cochlear and thyroid pathology are required to secure the diagnosis, it is unclear whether the condition might present without the classical features. The perchlorate discharge test, the gold-standard investigation for Pendred syndrome, is non-specific, and in the absence of alternative means of confirming the diagnosis, its sensitivity is unknown. We used the recent mapping of the gene to chromosome 7q to identify pedigrees with a likely diagnosis of Pendred syndrome, and assessed the prevalence of clinical parameters of disease in affected patients. Thirty-six familial cases showed co-segregation between disease and the Pendred syndrome locus on chromosome 7q. Clinical and investigative findings were compared in index cases (n = 18) vs. affected siblings (n = 18). The overall prevalence of goitre was 73%, higher in index cases (94%) than in siblings (56%), many of whom had not previously been considered to have the condition. One perchlorate discharge test was false-negative (2.9%). Radiological malformations of the cochlea were identified in 86% of cases. Securing a diagnosis of Pendred syndrome may be difficult, especially in the single case. The perchlorate discharge test, although valuable, is difficult to undertake in the younger patient, and radiology may assist in diagnosing such patients.
Adolescent↗
Pendred syndrome: evidence for genetic homogeneity and further refinement of linkage.
Pendred syndrome is the association between congenital sensorineural deafness and goitre. The disorder is characterised by the incomplete discharge of radioiodide from a primed thyroid following perchlorate challenge. However, the molecular basis of the association between hearing loss and a defect in organification of iodide remains unclear. Pendred syndrome is inherited as an autosomal recessive trait and has recently been mapped to 7q31 coincident with the non-syndromic deafness locus DFNB4. To define the critical linkage interval for Pendred syndrome we have studied five kindreds, each with members affected by Pendred syndrome. All families support linkage to the chromosome 7 region, defined by the microsatellite markers D7S501-D7S523. Detailed haplotype analysis refines the Pendred syndrome linkage interval to a region flanked by the marker loci D7S501 and D7S525, separated by a genetic distance estimated to be 2.5 cM. As potential candidate genes have as yet not been mapped to this interval, these data will contribute to a positional cloning approach for the identification of the Pendred syndrome gene.
Adolescent↗
Fluorescent in situ hybridisation (FISH) for hemizygous deletion at the elastin locus in patients with isolated supravalvular aortic stenosis.
Both Williams syndrome and isolated supravalvular aortic stenosis (SVAS) are caused by mutations at the elastin locus. Deletion demonstrable by FISH is the hallmark of Williams syndrome, whereas the mutations reported so far in SVAS have been more subtle. FISH positive elastin hemizygosity has not been reported in isolated SVAS. This report records our experience of FISH for elastin deletion in isolated SVAS and specifically reports a patient with non-Williams related SVAS, positive for the elastin deletion by FISH.
Adolescent↗
Craniosynostosis associated with FGFR3 pro250arg mutation results in a range of clinical presentations including unisutural sporadic craniosynostosis.
Several mutations involving the fibroblast growth factor receptor (FGFR) gene family have been identified in association with phenotypically distinct forms of craniosynostosis. One such point mutation, resulting in the substitution of proline by arginine in a critical region of the linker region between the first and second immunoglobulin-like domains, is associated with highly specific phenotypic consequences in that mutation at this point in FGFR1 results in Pfeiffer syndrome and analogous mutation in FGFR2 results in Apert syndrome. We now show that a much more variable clinical presentation accompanies analogous mutation in the FGFR3 gene. Specifically, mental retardation, apparently unrelated to the management of the craniosynostosis, appears to be a variable clinical consequence of this FGFR3 mutation.
Acrocephalosyndactylia↗
Hemihypertrophy, hemimegalencephaly, and polydactyly.
We present clinical and neuropathological details of a patient with hemihypertrophy and hemimegalencephaly who may have Proteus syndrome. The observation of polysyndactyly in the case indicates either that polysyndactyly is a rare manifestation in Proteus syndrome, or that a separate condition, mimicking Proteus syndrome and pursuing a similar clinical course, might exist.
Brain↗
Lumpers, splitters, and FGFRs.
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Craniofacial Dysostosis↗
Fibroblast growth factor receptor-2 mutations in craniosynostosis.
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Alternative Splicing↗
Skeletal dysplasias detectable by DNA analysis.
The emerging data of the last few years outlining the molecular basis of skeletal dysplasias has been instructive in several respects. The number of genetic loci involved appears to be much fewer than anticipated. This is offset by the identification of several instances where phenotypically distinct entities are found to be allelic variants. With respect to diagnosis by DNA, most of the conditions recognized have several different mutations described. Consequently, while mutation analysis may be possible in a given case, close liaison with the investigating laboratory is essential if optimal results are to be obtained. Achondroplasia is unusual in that there is a common mutation and the other mutations related to the phenotype appear to cluster to a few codons. This review highlights the relationship between phenotypes of skeletal malformation, their underlying loci and mutations. These mutations appear to mediate their phenotypic effects through a diverse range of genetic mechanisms.
Bone Diseases, Developmental↗
Pendred syndrome (goitre and sensorineural hearing loss) maps to chromosome 7 in the region containing the nonsyndromic deafness gene DFNB4.
Inherited causes account for about 50% of individuals presenting with childhood (prelingual) hearing loss, of which 70% are due to mutation in numerous single genes which impair auditory function alone (non-syndromic). The remainder are associated with other developmental anomalies termed syndromic deafness. Genes responsible for syndromic forms of hearing loss include the COL4A5 gene in Alport syndrome and the PAX3 and MITF genes in Waardenburg syndrome. Pendred syndrome is an autosomal recessive disorder associated with developmental abnormalities of the cochlea, sensorineural hearing loss and diffuse thyroid enlargement (goitre). Pendred syndrome is the most common syndromal form of deafness, yet the primary defect remains unknown. We have established a panel of 12 families with two or more affected individuals and used them to search for the location of the Pendred gene by linkage analysis. We excluded localization to four previously mapped nonsyndromic deafness loci but obtained conclusive evidence for linkage of the Pendred syndrome gene to microsatellite markers on chromosome 7q31 (D7S495 Zmax 7.32, Qmax = 0). This region contains a gene, DFNBL, for autosomal recessive non-syndromic sensorineural hearing loss. Multipoint analysis indicates that DFNB4 and Pendred syndrome co-localize to the same 5.5 centiMorgan (cM) interval flanked by D7S501 and D7S523. These data raise the possibility that Pendred syndrome is either allelic with DFNB4 or may represent an inherited contiguous gene disorder, not clinically manifest in the heterozygote.
Chromosome Mapping↗
Thyroid peroxidase: evidence for disease gene exclusion in Pendred's syndrome.
OBJECTIVE: Pendred's syndrome is an association between congenital neurosensory deafness and goitre with abnormal discharge of iodide following perchlorate challenge, indicating a defect of iodide organification. Although Pendred's syndrome may cause up to 7.5% of all cases of congenital deafness, the molecular basis of the association between the hearing loss and the thyroid organification defect remains unknown. We chose to investigate the role of the thyroid peroxidase (TPO) gene as the genetic defect in Pendred's syndrome. DESIGN: A highly informative variable number tandem repeat (VNTR), located 1.5 kb downstream of exon 10 of the TPO gene, was used to search for genetic linkage in multiple sibships affected by Pendred's syndrome. PATIENTS: Seven kindreds were recruited from the UK, each with at least two affected members. We have also examined a large inbred Israeli family with two affected offspring and five unaffected children. MEASUREMENTS: Individuals were assigned affected status based on the characteristic clinical features of Pendred's syndrome, namely the presence of congenital sensorineural hearing loss and the appearance in early life of a goitre. Additionally, at least one affected member from each sibship had a characteristic positive perchlorate discharge test (Morgans & Trotter, 1958). PCR amplification of genomic DNA at the TPO VNTR allowed assignment of genotypes to each individual and the calculation of a two-point LOD score. RESULTS: In six of the nine sibships analysed we found obligatory recombination between TPO and Pendred's syndrome. Non-complementation observed in affected parents with an affected offspring excluded TPO in an affected sibship with genotype sharing and supports a hypothesis of genetic homogeneity for Pendred's syndrome. In two sibships, mutation of the TPO gene as the cause of Pendred's syndrome could not be excluded. CONCLUSIONS: These data suggest that defects at the thyroid peroxidase locus on chromosome 2 are not the major cause of Pendred's syndrome.
Base Sequence↗
Pendred syndrome.
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Chromosomes, Human, Pair 7↗
A recurrent mutation, ala391glu, in the transmembrane region of FGFR3 causes Crouzon syndrome and acanthosis nigricans.
Mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have previously been identified in Crouzon syndrome, an autosomal dominant condition involving premature fusion of the cranial sutures. Several different missense and other mutations have been identified in Crouzon syndrome patients, clustering around the third immunoglobulin-like domain. We report here the identification of a mutation in the transmembrane region of FGFR3, common to three unrelated patients with classical Crouzon syndrome and acanthosis nigricans, a dermatological condition associated with thickening and abnormal pigmentation of the skin. The mutation within the FGFR3 transcript was determined by direct sequencing as a specific gcg to gag transversion, resulting in an amino acid substitution ala391glu within the transmembrane region.
Acanthosis Nigricans↗
Spectrum of craniosynostosis phenotypes associated with novel mutations at the fibroblast growth factor receptor 2 locus.
The causative relationship between several of the syndromic forms of craniosynostosis and mutations in the fibroblast growth factor receptor (FGFR) loci is now well established. However, within the group of patients with craniosynostosis, there are several families and sporadic cases whose clinical features differ in variable degrees from the classically described syndromes of craniosynostosis. In this communication we present novel FGFR2 mutations associated with a spectrum of craniosyostosis phenotypes in 4 sporadic cases and in one family in which craniosynostosis segregates. The mutation and phenotype data presented emphasise the clinical variability of mutations at this locus and underline the plasticity of the phenotype-genotype relationship in this important group of congenital malformation syndromes. Mutations found were tyrosine 105 to cysteine, glycine 338 to glutamic acid, serine 351 to cysteine and glycine 384 to arginine. These are the first reported mutations in the first immunoglobulin-like loop (tyrosine 105 to cysteine) and the transmembrane domain (glycine 384 to arginine) of FGFR2, providing further insights into the mechanism of abnormal receptor function in FGFR2 mutations.
Craniosynostoses↗
Nonspecific X-linked mental retardation with macrocephaly and obesity: a further family.
The phenotypic nonspecificity of many forms of X-linked mental retardation has hampered attempts to classify them into clinically homogeneous groups. One such condition, described by Clark and Baraitser [1987: Am J Med Genet 26:13-15], has been the subject of a single pedigree report to date. We now describe a further pedigree whose affected members share many manifestations with those reported by Clark and Baraitser, and we consider the possible distinction between this condition and Atkin-Flaitz syndrome.
Brain↗
Male pseudohermaphroditism in sibs with the alpha-thalassemia/mental retardation (ATR-X) syndrome.
Genital abnormalities have been noted in several patients with the X-linked form of alpha-thalassemia and mental retardation syndrome (ATR-X). The initial clinical report of the condition documented a phenotypic female with 46,XY karyotype. To this we now add 2 further siblings with abnormalities of the external genitalia, manifesting as male pseudohermaphroditism.
Abnormalities, Multiple↗