title: A distinct X-linked syndrome involving joint contractures, keloids, large optic cup-to-disc ratio, and renal stones results from a filamin A (FLNA) mutation.
abstract: We further evaluated a previously reported family with an apparently undescribed X-linked syndrome involving joint contractures, keloids, an increased optic cup-to-disc ratio, and renal stones to elucidate the genetic cause. To do this, we obtained medical histories and performed physical examination on 14 individuals in the family, five of whom are affected males and three are obligate carrier females. Linkage analysis was performed on all but one individual and chromosome X-exome sequencing was done on two affected males. The analysis localized the putative gene to Xq27-qter and chromosome X-exome sequencing revealed a mutation in exon 28 (c.4726G>A) of the filamin A (FLNA) gene, predicting that a conserved glycine had been replaced by arginine at amino acid 1576 (p.G1576R). Segregation analysis demonstrated that all known carrier females tested were heterozygous (G/A), all affected males were hemizygous for the mutation (A allele) and all normal males were hemizygous for the normal G allele. The data and the bioinformatic analysis indicate that the G1576R mutation in the FLNA gene is very likely pathogenic in this family. The syndrome affecting the family shares phenotypic overlap with other syndromes caused by FLNA mutations, but appears to be a distinct phenotype, likely representing a unique genetic syndrome.
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Melissa
authors.initials: M
authors.lastname: Lah
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Tejasvi
authors.initials: T
authors.lastname: Niranjan
authors.affiliation: Greenwood Genetic Center, Greenwood, South Carolina.
authors.forename: Sujata
authors.initials: S
authors.lastname: Srikanth
authors.affiliation: Greenwood Genetic Center, Greenwood, South Carolina.
authors.forename: Lynda
authors.initials: L
authors.lastname: Holloway
authors.affiliation: Greenwood Genetic Center, Greenwood, South Carolina.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: David D
authors.initials: DD
authors.lastname: Weaver
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002648:Child; D059472:Exome; D064448:Filamins / Q000235:genetics*; D056726:Genetic Association Studies; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis* / Q000235:genetics*; D008040:Genetic Linkage; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D013577:Syndrome; D049951:X Chromosome Inactivation; D055815:Young Adult
chemical_list: D064448:Filamins
keywords: FLNA; X-linked; contractures; filamin A; increased optic cup-to-disc ratio; keloids; uric acid renal stones