Recurrence risks for Bardet-Biedl syndrome: Implications of locus heterogeneity.
OBJECTIVE
Bardet-Biedl syndrome is a pleiotropic multiple anomaly syndrome inherited in an autosomal recessive pattern. It is now known that this disorder has locus heterogeneity, with causative mutations identified in as many as 14 genes. The aim of this study was to derive locus-specific recurrence risk estimates for family members of a proband affected with Bardet-Biedl syndrome.


METHODS
Mutation data from 187 probands affected with Bardet-Biedl syndrome were used. The authors counted the relative proportion of families with mutations at each of 10 loci and estimated locus-specific carrier rates for mutations using Hardy-Weinberg principles and an aggregate population frequency of 1/100,000 for the phenotype. Locus-specific recurrence risks were calculated for relatives of an affected proband.


RESULTS
Locus-specific carrier frequencies range from 1/250 to 1/2200, and the risks for an offspring of the sibling of an affected individual range from 1/1,500 to 1/13,000. The estimate of this risk derived under a locus homogeneity model is 1/960.


CONCLUSIONS
Variation of recurrence risks of this magnitude may have implications for genetic counseling of families with affected individuals, in particular about prenatal testing and other reproductive options. Similar analyses to determine locus-specific carrier frequencies for other phenotypes with significant locus heterogeneity may yield similarly relevant results.
Sapp
Julie C
JC
National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. sappj@mail.nih.gov
Nishimura
Darryl
D
Johnston
Jennifer J
JJ
Stone
Edwin M
EM
Héon
Elise
E
Sheffield
Val C
VC
Biesecker
Leslie G
LG
D000015:Abnormalities, Multiple / Q000235:genetics; D000483:Alleles; D020788:Bardet-Biedl Syndrome / Q000175:diagnosis* / Q000235:genetics*; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D006580:Genetic Carrier Screening; D018740:Genetic Heterogeneity; D056426:Genetic Loci; D005820:Genetic Testing; D006579:Heterozygote; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D009765:Obesity; D010375:Pedigree; D011296:Prenatal Diagnosis; D012174:Retinitis Pigmentosa; D018570:Risk Assessment