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


RESULTS
Whole-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.


CONCLUSIONS
Our 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.
Christian R
CR
Marshall
Sandra A
SA
Farrell
Donna
D
Cushing
Tara
T
Paton
Tracy L
TL
Stockley
Dimitri J
DJ
Stavropoulos
Peter N
PN
Ray
Michael
M
Szego
Lynette
L
Lau
Sergio L
SL
Pereira
Ronald D
RD
Cohn
Richard F
RF
Wintle
Adel M
AM
Abuzenadah
Muhammad
M
Abu-Elmagd
Stephen W
SW
Scherer
D001344:Autopsy; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D004392:Dwarfism / Q000175:diagnosis* / Q000235:genetics*; D059472:Exome; D005260:Female; D005333:Fetus / Q000378:metabolism*; D016368:Frameshift Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D009123:Muscle Hypotonia / Q000175:diagnosis* / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011247:Pregnancy; D013131:Spine / Q000002:abnormalities*
D003598:Cytoskeletal Proteins; C522000:OBSL1 protein, human