PMID- 10618407
OWN - NLM
STAT- MEDLINE
DCOM- 20000210
LR  - 20220331
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 97
IP  - 1
DP  - 2000 Jan 4
TI  - A human model for multigenic inheritance: phenotypic expression in Hirschsprung
      disease requires both the RET gene and a new 9q31 locus.
PG  - 268-73
AB  - Reduced penetrance in genetic disorders may be either dependent or independent of
      the genetic background of gene carriers. Hirschsprung disease (HSCR) demonstrates
      a complex pattern of inheritance with approximately 50% of familial cases being
      heterozygous for mutations in the receptor tyrosine kinase RET. Even when
      identified, the penetrance of RET mutations is only 50-70%, gender-dependent, and
      varies with the extent of aganglionosis. We searched for additional
      susceptibility genes which, in conjunction with RET, lead to phenotypic
      expression by studying 12 multiplex HSCR families. Haplotype analysis and
      extensive mutation screening demonstrated three types of families: six families
      harboring severe RET mutations (group I); and the six remaining families, five of
      which are RET-linked families with no sequence alterations and one RET-unlinked
      family (group II). Although the presence of RET mutations in group I families is 
      sufficient to explain HSCR inheritance, a genome scan reveals a new
      susceptibility locus on 9q31 exclusively in group II families. As such, the gene 
      at 9q31 is a modifier of HSCR penetrance. These observations imply that
      identification of new susceptibility factors in a complex disease may depend on
      classification of families by mutational type at known susceptibility genes.
FAU - Bolk, S
AU  - Bolk S
AD  - Department of Genetics, Case Western Reserve University School of Medicine,
      Cleveland OH 44106, USA.
FAU - Pelet, A
AU  - Pelet A
FAU - Hofstra, R M
AU  - Hofstra RM
FAU - Angrist, M
AU  - Angrist M
FAU - Salomon, R
AU  - Salomon R
FAU - Croaker, D
AU  - Croaker D
FAU - Buys, C H
AU  - Buys CH
FAU - Lyonnet, S
AU  - Lyonnet S
FAU - Chakravarti, A
AU  - Chakravarti A
LA  - eng
GR  - R01 HD028088/HD/NICHD NIH HHS/United States
GR  - R37 HD028088/HD/NICHD NIH HHS/United States
GR  - HD28088/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Drosophila Proteins)
RN  - 0 (Genetic Markers)
RN  - 0 (Proto-Oncogene Proteins)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-ret)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Ret protein, Drosophila)
SB  - IM
MH  - Chromosomes, Human, Pair 9/*genetics
MH  - *Drosophila Proteins
MH  - Female
MH  - Genetic Linkage
MH  - Genetic Markers
MH  - Haplotypes
MH  - Hirschsprung Disease/*genetics
MH  - Humans
MH  - Lod Score
MH  - Male
MH  - Models, Genetic
MH  - Mutation
MH  - Pedigree
MH  - Penetrance
MH  - Phenotype
MH  - Proto-Oncogene Proteins/*genetics
MH  - Proto-Oncogene Proteins c-ret
MH  - RNA Splicing/genetics
MH  - Receptor Protein-Tyrosine Kinases/*genetics
MH  - Statistics, Nonparametric
PMC - PMC26652
EDAT- 2000/01/05 00:00
MHDA- 2000/01/05 00:01
CRDT- 2000/01/05 00:00
PHST- 2000/01/05 00:00 [pubmed]
PHST- 2000/01/05 00:01 [medline]
PHST- 2000/01/05 00:00 [entrez]
AID - 10.1073/pnas.97.1.268 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):268-73. doi: 10.1073/pnas.97.1.268.