Prenatal testing for a novel EBP missense mutation causing X-linked dominant chondrodysplasia punctata.
OBJECTIVE
To determine the pathogenicity of a novel conserved missense mutation, p.Ser98Phe, in the emopamil binding protein (EBP) gene in order to perform a prenatal diagnostic test for X-linked dominant chondrodysplasia punctata (CDPX2) in a male foetus at 50% risk.


METHODS
Family members were tested for p.Ser98Phe using PCR and sequence analysis of leucocyte or buccal cell DNA. Haplotype analysis was employed to identify the grandparental chromosome on which p.Ser98Phe had arisen. In silico protein analyses were used to predict whether p.Ser98Phe significantly altered the EBP protein structure.


RESULTS
The mutation was detected in the proband and her affected mother but not in the maternal grandmother, who was thought to be mildly affected. However, haplotype analysis showed that p.Ser98Phe had arisen de novo on the grandpaternal X chromosome. Protein secondary structure predictions suggested that p.Ser98Phe alters the properties of the helix within which it is located.


CONCLUSIONS
We concluded that p.Ser98Phe is likely to be pathogenic and proceeded with prenatal testing. The male foetus had not inherited p.Ser98Phe and his unaffected status was confirmed at birth. This family demonstrates some of the difficulties in interpreting the significance of novel missense mutations, particularly when results are needed urgently for prenatal diagnosis.
Tysoe
Carolyn
C
Department of Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK.
Law
Caroline J
CJ
Caswell
Richard
R
Clayton
Peter
P
Ellard
Sian
S
D002806:Chondrodysplasia Punctata / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005817:Genetic Counseling; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011247:Pregnancy; D011296:Prenatal Diagnosis; D013251:Steroid Isomerases / Q000235:genetics*
D013251:Steroid Isomerases; C090445:EBP protein, human