title: From a single whole exome read to notions of clinical screening: primary ciliary dyskinesia and RSPH9 p.Lys268del in the Arabian Peninsula.
abstract: Primary ciliary dyskinesia (PCD) is a genetic disorder, usually autosomal recessive, causing early respiratory disease and later subfertility. Whole exome sequencing may enable efficient analysis for locus heterogeneous disorders such as PCD. We whole-exome-sequenced one consanguineous Saudi Arabian with clinically diagnosed PCD and normal laterality, to attempt ab initio molecular diagnosis. We reviewed 13 known PCD genes and potentially autozygous regions (extended homozygosity) for homozygous exon deletions, non-dbSNP codon, splice-site base variants or small indels. Homozygous non-dbSNP changes were also reviewed exome-wide. One single molecular read representing RSPH9 p.Lys268del was observed, with no wild-type reads, and a notable deficiency of mapped reads at this location. Among all observations, RSPH9 was the strongest candidate for causality. Searching unmapped reads revealed seven more mutant reads. Direct assay for p.Lys268del (MboII digest) confirmed homozygosity in the affected individual, then confirmed homozygosity in three siblings with bronchiectasis. Our finding in southwest Saudi Arabia indicates that p.Lys268del, previously observed in two Bedouin families (Israel, UAE), is geographically widespread in the Arabian Peninsula. Analogous with cystic fibrosis CFTR p.Phe508del, screening for RSPH9 p.Lys268del (which lacks sentinel dextrocardia) in those at risk would help in early diagnosis, tailored clinical management, genetic counselling and primary prevention.
authors.affiliation: College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Muslim M
authors.initials: MM
authors.lastname: Alsaadi
authors.forename: Tom R
authors.initials: TR
authors.lastname: Gaunt
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Boustred
authors.forename: Philip A I
authors.initials: PA
authors.lastname: Guthrie
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.forename: Luca
authors.initials: L
authors.lastname: Lenzi
authors.forename: Lucille
authors.initials: L
authors.lastname: Rainbow
authors.forename: Neil
authors.initials: N
authors.lastname: Hall
authors.forename: Khalid K
authors.initials: KK
authors.lastname: Alharbi
authors.forename: Ian N M
authors.initials: IN
authors.lastname: Day
mesh_terms: D003241:Consanguinity; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome; D006801:Humans; D007619:Kartagener Syndrome / Q000235:genetics*; D009154:Mutation; D012529:Saudi Arabia; D017422:Sequence Analysis, DNA
chemical_list: D003598:Cytoskeletal Proteins; C573132:RSPH9 protein, human