title: Intellectual disability, midface hypoplasia, facial hypotonia, and Alport syndrome are associated with a deletion in Xq22.3.
abstract: Alport syndrome with intellectual disability (ID) is a contiguous gene deletion syndrome involving several genes on Xq22.3 including COL4A5 and ACSL4. We report on a family with two males with this disorder and a Xq22.3 deletion. Fluorescent in situ hybridization and genomic analyses mapped the deletion region to between exon 1 of COL4A5 and exon 12 of ACSL4. The patients' mother has microscopic hematuria and was found to be heterozygous for the Xq22.3 deletion. Analysis using reverse transcription polymerase chain reaction of lymphoblastoid cell line RNA from an affected male in the family revealed a stable chimeric transcript with the ACSL4 exons 13-17 replaced by a cryptic exon from intron 1 of the COL4A5 gene. A truncated 54 kDa protein was predicted from this transcript but Western blot analysis and ACSL4 enzyme assay both showed functional nullisomy of ACSL4. We also compared the clinical features of the family with three previously reported families with the ACSL4 gene deletion and found that ID with absent or severely delayed speech, midface hypoplasia, and facial hypotonia are consistent features observed in the absence of ACSL4 gene.
authors.affiliation: JC Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina, USA.
authors.forename: Jayson D
authors.initials: JD
authors.lastname: Rodriguez
authors.forename: Shambhu S
authors.initials: SS
authors.lastname: Bhat
authors.forename: Ilaria
authors.initials: I
authors.lastname: Meloni
authors.forename: Sydney
authors.initials: S
authors.lastname: Ladd
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Leslie
authors.forename: Emanuel O
authors.initials: EO
authors.lastname: Doyne
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
authors.forename: Barbara R
authors.initials: BR
authors.lastname: Dupont
authors.forename: Roger E
authors.initials: RE
authors.lastname: Stevenson
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.forename: Anand K
authors.initials: AK
authors.lastname: Srivastava
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D002675:Child, Preschool; D002872:Chromosome Deletion; D041321:Chromosomes, Human, X / Q000235:genetics*; D003066:Coenzyme A Ligases / Q000235:genetics; D024141:Collagen Type IV / Q000235:genetics; D004252:DNA Mutational Analysis; D019066:Facies; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007805:Language Development Disorders / Q000235:genetics; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D009394:Nephritis, Hereditary / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: C478159:COL4A5 protein, human; D024141:Collagen Type IV; D003066:Coenzyme A Ligases; D000098859:Long-Chain-Fatty-Acid-CoA Ligase