Segregation Analysis in Shwachman-Diamond Syndrome: Evidence for Recessive Inheritance

Shwachman-Diamond syndrome is a rare disorder of unknown cause. Reports have indicated the occurrence of affected siblings, but formal segregation analysis has not been performed. In families collected for genetic studies, the mean paternal age and mean difference in parental ages were found to be c...

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Bibliographic Details
Published in:American journal of human genetics 2000-04, Vol.66 (4), p.1413-1416
Main Authors: Ginzberg, H., Shin, J., Ellis, L., Goobie, S., Morrison, J., Corey, M., Durie, P.R., Rommens, J.M.
Format: Article
Language:English
Subjects:
Abnormalities, Multiple - blood
Abnormalities, Multiple - genetics
Abnormalities, Multiple - physiopathology
Adolescent
Adult
Algorithms
Biological and medical sciences
Child
Child, Preschool
Cohort Studies
Complex syndromes
Computer Simulation
Exocrine Pancreatic Insufficiency - blood
Exocrine Pancreatic Insufficiency - genetics
Exocrine Pancreatic Insufficiency - physiopathology
Family Health
Female
Genes, Recessive - genetics
Genetic Heterogeneity
Hematologic Diseases - blood
Hematologic Diseases - genetics
Hematologic Diseases - physiopathology
Heterozygote
Humans
Infant
Male
Medical genetics
Medical sciences
Models, Genetic
Paternal Age
Phenotype
Recessive inheritance
Segregation analysis
Shwachman-Diamond syndrome
Syndrome
Trypsinogen - blood
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Summary:Shwachman-Diamond syndrome is a rare disorder of unknown cause. Reports have indicated the occurrence of affected siblings, but formal segregation analysis has not been performed. In families collected for genetic studies, the mean paternal age and mean difference in parental ages were found to be consistent with the general population. We determined estimates of segregation proportion in a cohort of 84 patients with complete sibship data under the assumption of complete ascertainment, using the Li and Mantel estimator, and of single ascertainment with the Davie modification. A third estimate was also computed with the expectation-maximization (EM) algorithm. All three estimates supported an autosomal recessive mode of inheritance, but complete ascertainment was found to be unlikely. Although there are no overt signs of disease in adult carriers (parents), the use of serum trypsinogen levels to indicate exocrine pancreatic dysfunction was evaluated as a potential measure for heterozygote expression. No consistent differences were found in levels between parents and a normal control population. Although genetic heterogeneity cannot be excluded, our results indicate that simulation and genetic analyses of Shwachman-Diamond syndrome should consider a recessive model of inheritance.
ISSN:0002-9297
1537-6605
DOI:10.1086/302856