Partial uniparental isodisomy of chromosome 16 unmasks a deleterious biallelic mutation in IFT140 that causes Mainzer-Saldino syndrome

dc.contributor.authorHelm, Benjamin M.
dc.contributor.authorWiller, Jason R.
dc.contributor.authorSadeghpour, Azita
dc.contributor.authorGolzio, Christelle
dc.contributor.authorCrouch, Eric
dc.contributor.authorVergano, Samantha Schrier
dc.contributor.authorKatsanis, Nicholas
dc.contributor.authorDavis, Erica E.
dc.contributor.departmentMedical and Molecular Genetics, School of Medicineen_US
dc.date.accessioned2018-05-10T19:49:22Z
dc.date.available2018-05-10T19:49:22Z
dc.date.issued2017-07-19
dc.description.abstractBACKGROUND: The ciliopathies represent an umbrella group of >50 clinical entities that share both clinical features and molecular etiology underscored by structural and functional defects of the primary cilium. Despite the advances in gene discovery, this group of entities continues to pose a diagnostic challenge, in part due to significant genetic and phenotypic heterogeneity and variability. We consulted a pediatric case from asymptomatic, non-consanguineous parents who presented as a suspected ciliopathy due to a constellation of retinal, renal, and skeletal findings. RESULTS: Although clinical panel sequencing of genes implicated in nephrotic syndromes yielded no likely causal mutation, an oligo-SNP microarray identified a ~20-Mb region of homozygosity, with no altered gene dosage, on chromosome 16p13. Intersection of the proband's phenotypes with known disease genes within the homozygous region yielded a single candidate, IFT140, encoding a retrograde intraflagellar transport protein implicated previously in several ciliopathies, including the phenotypically overlapping Mainzer-Saldino syndrome (MZSDS). Sanger sequencing yielded a maternally inherited homozygous c.634G>A; p.Gly212Arg mutation altering the exon 6 splice donor site. Functional studies in cells from the proband showed that the locus produced two transcripts: a majority message containing a mis-splicing event that caused a premature termination codon and a minority message homozygous for the p.Gly212Arg allele. Zebrafish in vivo complementation studies of the latter transcript demonstrated a loss of function effect. Finally, we conducted post-hoc trio-based whole exome sequencing studies to (a) test the possibility of other causal loci in the proband and (b) explain the Mendelian error of segregation for the IFT140 mutation. We show that the proband harbors a chromosome 16 maternal heterodisomy, with segmental isodisomy at 16p13, likely due to a meiosis I error in the maternal gamete. CONCLUSIONS: Using clinical phenotyping combined with research-based genetic and functional studies, we have characterized a recurrent IFT140 mutation in the proband; together, these data are consistent with MZSDS. Additionally, we report a rare instance of a uniparental isodisomy unmasking a deleterious mutation to cause a ciliary disorder.en_US
dc.eprint.versionFinal published versionen_US
dc.identifier.citationHelm, B. M., Willer, J. R., Sadeghpour, A., Golzio, C., Crouch, E., Vergano, S. S., … Davis, E. E. (2017). Partial uniparental isodisomy of chromosome 16 unmasks a deleterious biallelic mutation in IFT140 that causes Mainzer-Saldino syndrome. Human Genomics, 11, 16. http://doi.org/10.1186/s40246-017-0111-9en_US
dc.identifier.urihttps://hdl.handle.net/1805/16152
dc.language.isoen_USen_US
dc.publisherBMCen_US
dc.relation.isversionof10.1186/s40246-017-0111-9en_US
dc.relation.journalHuman Genomicsen_US
dc.rightsAttribution 3.0 United States
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/
dc.sourcePMCen_US
dc.subjectConorenal dysplasiaen_US
dc.subjectHeterodisomyen_US
dc.subjectIntraflagellar transporten_US
dc.subjectSkeletal ciliopathyen_US
dc.subjectWhole exome sequencingen_US
dc.subjectZebrafishen_US
dc.titlePartial uniparental isodisomy of chromosome 16 unmasks a deleterious biallelic mutation in IFT140 that causes Mainzer-Saldino syndromeen_US
dc.typeArticleen_US
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