Whole-exome analysis of foetal autopsy tissue reveals a frameshift mutation in OBSL1, consistent with a diagnosis of 3-M Syndrome.

Christian R Marshall,Muhammad Abu-Elmagd,Michael Szego,Stephen W Scherer,Richard F Wintle,Sandra A Farrell,Peter N Ray,Donna Cushing,Sergio L Pereira,Adel M Abuzenadah,Tracy L Stockley,Dimitri J Stavropoulos,Tara Paton,Lynette Lau,Ronald D Cohn

doi:10.1186/1471-2164-16-s1-s12

Abstract

BackgroundWe report a consanguineous couple that has experienced three consecutive pregnancy losses following the foetal ultrasound finding of short limbs. Post-termination examination revealed no skeletal dysplasia, but some subtle proximal limb shortening in two foetuses, and a spectrum of mildly dysmorphic features. Karyotype was normal in all three foetuses (46, XX) and comparative genomic hybridization microarray analysis detected no pathogenic copy number variants.ResultsWhole-exome sequencing and genome-wide homozygosity mapping revealed a previously reported frameshift mutation in the OBSL1 gene (c.1273insA p.T425nfsX40), consistent with a diagnosis of 3-M Syndrome 2 (OMIM #612921), which had not been anticipated from the clinical findings.ConclusionsOur study provides novel insight into the early clinical manifestations of this form of 3-M syndrome, and demonstrates the utility of whole exome sequencing as a tool for prenatal diagnosis in particular when there is a family history suggestive of a recurrent set of clinical symptoms.

Highlights

We report a consanguineous couple that has experienced three consecutive pregnancy losses following the foetal ultrasound finding of short limbs
Karyotyping, genome wide SNP genotyping, homozygosity mapping, and copy number variation (CNV) analysis DNA samples from all family members were isolated from whole blood or autopsy material
Prenatal diagnosis of 3-M syndrome based on ultrasound is findings is unreliable, given that intrauterine growth retardation has many causes and is not specific to this syndrome

Summary

Results

Homozygosity mapping using high-resolution genotyping revealed two regions that reached significance: one of 9.7 Mb at chromosome 2q34-q35, and one of 35.7 Mb at chromosome 8q13.2-q22.3 present for all three affected foetuses (Additional File 1, Table S1 and Figure S1). These regions were both heterozygous in the biological parents. The fifth pregnancy was tested in the clinical diagnostic laboratory, indicating the foetus was a carrier of the OBSL1 mutation This was consistent with the normal developmental pattern subsequently observed

Conclusions

Materials and methods

Discussion

Holder-Espinasse M