Expanding the phenotypic spectrum of ECEL1-related congenital contracture syndromes.

Using a combination of homozygosity mapping and whole-exome sequencing (WES), we identified a novel missense c.1819G>A mutation (G607S) in the endothelin-converting enzyme-like 1 (ECEL1) gene in a consanguineous pedigree of Turkish origin presenting with a syndrome of camptodactyly, scoliosis, limited knee flexion, significant refractive errors and ophthalmoplegia. ECEL1 mutations were recently reported to cause recessive forms of distal arthrogryposis. This report expands on the molecular basis and the phenotypic spectrum of ECEL1-associated congenital contracture syndromes.

Homozygous feature of isolated triphalangeal thumb-preaxial polydactyly linked to 7q36: no phenotypic difference between homozygotes and heterozygotes.

Preaxial polydactyly is a common limb malformation in humans with variable clinical expression. Different types of triphalangeal thumb-preaxial polydactyly phenotypes were mapped to the chromosome 7q36 region. We studied a large Turkish family of 69 individuals, of whom 22 individuals were affected. In all, 11 affected family members were clinically and radiologically evaluated. All affected individuals had a triphalangeal thumb and a preaxial (hypoplastic) extra digit bilaterally, with minimal intrafamilial variation. No feet involvement was observed. Linkage and haplotype analyses using 20 informative meioses confirmed the 7q36 region contained the LIMBR1 gene. Maximum logarithm of the odds (LOD) scores were obtained with DNA markers D7S550 and D7S2423. We have further identified a novel C to T alteration at position 4909 bp in the critical zone of polarizing activity regulatory sequence (ZRS) region, in the intron 5, of the LMBR1 gene. One affected male with homozygous status and no phenotypic difference from affected family members with heterozygous status represented the first homozygote case of the triphalangeal thumb-preaxial polydactyly phenotype.

Skewed X inactivation in an X linked nystagmus family resulted from a novel, p.R229G, missense mutation in the FRMD7 gene.

AIMS: This study aimed to identify the underlying genetic defect of a large Turkish X linked nystagmus (NYS) family. METHODS: Both Xp11 and Xq26 loci were tested by linkage analysis. The 12 exons and intron-exon junctions of the FRMD7 gene were screened by direct sequencing. X chromosome inactivation analysis was performed by enzymatic predigestion of DNA with a methylation-sensitive enzyme, followed by PCR of the polymorphic CAG repeat of the androgen receptor gene. RESULTS: The family contained 162 individuals, among whom 28 had NYS. Linkage analysis confirmed the Xq26 locus. A novel missense c.686C>G mutation, which causes the substitution of a conserved arginine at amino acid position 229 by glycine (p.R229G) in exon 8 of the FRMD7 gene, was observed. This change was not documented in 120 control individuals. The clinical findings in a female who was homozygous for the mutation were not different from those of affected heterozygous females. Skewed X inactivation was remarkable in the affected females of the family. CONCLUSIONS: A novel p.R229G mutation in the FRMD7 gene causes the NYS phenotype, and skewed X inactivation influences the manifestation of the disease in X linked NYS females.

An apparently dominant bipolar affective disorder (BPAD) locus on chromosome 20p11.2-q11.2 in a large Turkish pedigree.

Bipolar affective disorder (BPAD), also known as manic-depressive illness, is a common complex, polygenic disorder characterised by recurrent cyclic episodes of mania and depression. Family, twin, and adoption studies strongly suggest a genetic predisposition/susceptibility to BPAD, but no genes have yet been identified. We studied a large Turkish pedigree, with an apparently autosomal dominant BPAD, which contained 13 affected individuals. The age of onset ranged from 15-40 with a mean of 25 years. The phenotypes consisted of recurrent manic and major depressive episodes, including suicidal attempts; there was usually full remission with lithium treatment. A genome-wide linkage analysis using a dominant mode of inheritance showed strong evidence for a BPAD susceptibility locus on chromosome 20p11.2-q11.2. The highest 2-point lod score of 4.34 at theta = 0 was obtained with markers D20S604, D20S470, D20S836 and D20S838 using a dominant model with full penetrance. Haplotype analysis enabled the mapping of the BPAD locus in this family between markers D20S186 and D20S109, to a region of approximately 42 cM.

Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome.

Robinow syndrome is a short-limbed dwarfism characterized by abnormal morphogenesis of the face and external genitalia, and vertebral segmentation. The recessive form of Robinow syndrome (RRS; OMIM 268310), particularly frequent in Turkey, has a high incidence of abnormalities of the vertebral column such as hemivertebrae and rib fusions, which is not seen in the dominant form. Some patients have cardiac malformations or facial clefting. We have mapped a gene for RRS to 9q21-q23 in 11 families. Haplotype sharing was observed between three families from Turkey, which localized the gene to a 4. 9-cM interval. The gene ROR2, which encodes an orphan membrane-bound tyrosine kinase, maps to this region. Heterozygous (presumed gain of function) mutations in ROR2 were previously shown to cause dominant brachydactyly type B (BDB; ref. 7). In contrast, Ror2-/- mice have a short-limbed phenotype that is more reminiscent of the mesomelic shortening observed in RRS. We detected several homozygous ROR2 mutations in our cohort of RRS patients that are located upstream from those previously found in BDB. The ROR2 mutations present in RRS result in premature stop codons and predict nonfunctional proteins.

Clinical and genetic studies on 12 preaxial polydactyly families and refinement of the localisation of the gene responsible to a 1.9 cM region on chromosome 7q36.

Polydactyly is the most frequently observed congenital hand malformation with a prevalence between 5 and 19 per 10000 live births. It can occur as an isolated disorder, in association with other hand/foot malformations, or as a part of a syndrome, and is usually inherited as an autosomal dominant trait. According to its anatomical location, polydactyly can be generally subdivided into pre- and postaxial forms. Recently, a gene responsible for preaxial polydactyly types II and III, as well as complex polysyndactyly, has been localised to chromosome 7q36. In order to facilitate the search for the underlying genetic defect, we ascertained 12 additional families of different ethnic origin affected with preaxial polydactyly. Eleven of the kindreds investigated could be linked to chromosome 7q36, enabling us to refine the critical region for the preaxial polydactyly gene to a region of 1.9 cM. Our findings also indicate that radial and tibial dysplasia/aplasia can be associated with preaxial polydactyly on chromosome 7q36. Combining our results with other studies suggests that all non-syndromic preaxial polydactylies associated with triphalangism of the thumb are caused by a single genetic locus, but that there is genetic heterogeneity for preaxial polydactyly associated with duplications of biphalangeal thumbs. Comparison of the phenotypic and genetic findings of different forms of preaxial polydactyly is an important step in analysing and understanding the aetiology and pathogenesis of these limb malformations.

A large family with type IV radial polydactyly.

This study examines one of the largest pedigrees with radial polydactyly type IV (uncomplicated polysyndactyly) comprising a total of 69 individuals, of whom 26 have been affected over six generations. Typical manifestations of the pedigree were bilateral radial and ulnar digital duplications, as well as syndactyly between the middle and ring fingers and the second and third toes. There was no craniofacial anomaly in any of the 17 cases examined physically. This observation suggests that radial polydactyly type IV and Greig craniofacial-synostosis syndrome with similar digital manifestations are clinically-distinct entities.

Genetic features of retinitis pigmentosa in Turkey.

Sixty-two cases with retinitis pigmentosa from 42 index families were investigated to reveal the genetic features of the disease in Turkey. There were 42 propositi of whom 5 had a systemic syndrome associated with retinitis pigmentosa. Of the remaining 37 cases the condition was autosomal recessive in 21 (56.8%), sporadic in 12 (32.4%), autosomal dominant in 3 (8.1%) and X-linked recessive in one (2.7%). Sporadic cases may be more frequent as many hereditary cases are not brought to medical attention in rural families. Male preponderance among sporadic cases may indicate that there may be more X-linked cases. Nine out of 21 cases initially classified as sporadic displayed parental consanguinity and they were included as having autosomal recessive trait. Large families with autosomal recessive inheritance may prove valuable in linkage analysis and in defining future gene abnormalities.

Therapeutical and genetical aspects of congenital glaucomas.

Therapy for congenital glaucoma is primarily surgical. We have investigated 249 cases who have undergone trabeculectomy. There was a 79% success rate as regards to control of the IOP. Vision could be saved among the patients who had applied relatively early. At the end of the follow up which was 5 years IOP remained normal in the successful group. All the patients and their families were analysed genetically by their pedigrees and caryotypes. An autosomal recessive pattern with variable penetrance was found. The majority of the patients came from families with consanguineous marriages giving a rate of 66.6%. It was suggested that the course of the disease is highly affected by and related to parental consanguinity. An early age of onset and an accelerated clinical course could be well correlated.