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

Marshall CR, Farrell SA, Cushing D, Paton T, Stockley TL, Stavropoulos DJ, Ray PN, Szego M, Lau L, Pereira SL, Cohn RD, Wintle RF, Abuzenadah AM, Abu-Elmagd M, Scherer SW - BMC Genomics (2015)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Pedigree with segregation of OBSL1 c.1273insA variant (p.T425nfsX40) in four elective terminations. Individuals 1-5 were genotyped with high-resolution SNP microarray analysis with subsequent homozygosity mapping. Individuals 3 and 4 underwent whole exome sequencing. Individuals 6 and 7 underwent targeted variant testing in the clinical diagnostic laboratory.
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Figure 1: Pedigree with segregation of OBSL1 c.1273insA variant (p.T425nfsX40) in four elective terminations. Individuals 1-5 were genotyped with high-resolution SNP microarray analysis with subsequent homozygosity mapping. Individuals 3 and 4 underwent whole exome sequencing. Individuals 6 and 7 underwent targeted variant testing in the clinical diagnostic laboratory.

Mentions: We report a first cousin marriage consanguineous couple that experienced three consecutive pregnancy losses following the foetal ultrasound finding of short limbs (Figure 1). Clinical features are summarized in Table 1. The couple was seen in their first pregnancy initially because of an increased nuchal translucency (NT) measurement (5.2 mm at 13.5 weeks gestation). Amniocentesis showed normal female chromosomes (46, XX). Ultrasound examination at 19 weeks gestation (as estimated by last menstrual period (LMP) date and previous ultrasound) demonstrated normal foetal anatomy, but the femoral and humeral lengths lagged by two weeks. Bone morphology appeared normal, as was a foetal echocardiogram. Repeat ultrasounds at 25 weeks and 28 weeks showed foetal long bones lagging by four weeks and five weeks, respectively. The pregnancy was ended. Radiographs taken post-termination showed no evidence of a skeletal dysplasia. This fetus was not examined by a geneticist and nor was there an autopsy.


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

Marshall CR, Farrell SA, Cushing D, Paton T, Stockley TL, Stavropoulos DJ, Ray PN, Szego M, Lau L, Pereira SL, Cohn RD, Wintle RF, Abuzenadah AM, Abu-Elmagd M, Scherer SW - BMC Genomics (2015)

Pedigree with segregation of OBSL1 c.1273insA variant (p.T425nfsX40) in four elective terminations. Individuals 1-5 were genotyped with high-resolution SNP microarray analysis with subsequent homozygosity mapping. Individuals 3 and 4 underwent whole exome sequencing. Individuals 6 and 7 underwent targeted variant testing in the clinical diagnostic laboratory.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4315153&req=5

Figure 1: Pedigree with segregation of OBSL1 c.1273insA variant (p.T425nfsX40) in four elective terminations. Individuals 1-5 were genotyped with high-resolution SNP microarray analysis with subsequent homozygosity mapping. Individuals 3 and 4 underwent whole exome sequencing. Individuals 6 and 7 underwent targeted variant testing in the clinical diagnostic laboratory.
Mentions: We report a first cousin marriage consanguineous couple that experienced three consecutive pregnancy losses following the foetal ultrasound finding of short limbs (Figure 1). Clinical features are summarized in Table 1. The couple was seen in their first pregnancy initially because of an increased nuchal translucency (NT) measurement (5.2 mm at 13.5 weeks gestation). Amniocentesis showed normal female chromosomes (46, XX). Ultrasound examination at 19 weeks gestation (as estimated by last menstrual period (LMP) date and previous ultrasound) demonstrated normal foetal anatomy, but the femoral and humeral lengths lagged by two weeks. Bone morphology appeared normal, as was a foetal echocardiogram. Repeat ultrasounds at 25 weeks and 28 weeks showed foetal long bones lagging by four weeks and five weeks, respectively. The pregnancy was ended. Radiographs taken post-termination showed no evidence of a skeletal dysplasia. This fetus was not examined by a geneticist and nor was there an autopsy.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus