Two-Generation Pyloric Stenosis

SUMMARY A large body of data on segregating families is used to generate specific recurrence risks conditional on sex and birth order for the best-fitting model of polygenes plus maternal effect. The method is general for diseases of complex inheritance, and lies within the competence of any serious genetic clinic. The question of whether consultees demand as much specificity should be subordinate to the question of whether counsellors are justified in providing less.Genetic counselling is a transaction which includes specification of a recurrence risk for a particular disease in a particular family, using parameters from segregation analysis of a larger body of data. This problem has been solved for simple cases (Murphy and Mutalik, 1969), and the utility of computer programmes to determine specific risks has been *demonstrated (Heuch and Li, 1972). It remains to generalise these prototypes to more complex pedi-*grees and modes ofinheritance.As a first step we here apply the mixed model of Morton and MacLean (1974) to a large body of data on pyloric stenosis, a disease of obscure and presumably complex aetiology whose incidence varies widely with sex, birth order, and ethnic group. The mixed model subsumes polygenes, major loci, and common environment. Application of the mixed model illustrates the power and specificity which complex segregation analysis brings to prediction of recurrence risks. Pyloric stenosisDiagnosis of a hypertrophic muscular tumour of the pylorus presents several problems. The tumour may be present without causing symptoms at any time (Carter and Powell, 1954). Distinction from pylorospasm is not clear.

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“…The tumour may be present without causing symptoms at any time (Carter and Powell, 1954). Distinction from pylorospasm is not clear.…”

Section: Pyloric Stenosismentioning

confidence: 98%

Recurrence risks in complex inheritance with special regard to pyloric stenosis.

Lalouel¹,

Morton²,

Maclean³

et al. 1977

Journal of Medical Genetics

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“…IHPS shows familial aggregation and represents a paradigm for the multifactorial sex-modiWed threshold model of inheritance, with aVected males outnumbering females in a 4:1 ratio (Carter 1961;Carter and Powell 1954). IHPS is predicted to be oligogenic, determined by two or three loci of moderate eVect estimated to confer individual genotype relative risks (GRRs) of up to 5 (Mitchell and Risch 1993).…”

Section: Introductionmentioning

confidence: 99%

Infantile hypertrophic pyloric stenosis: evaluation of three positional candidate genes, TRPC1, TRPC5 and TRPC6, by association analysis and re-sequencing

et al. 2009

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Infantile hypertrophic pyloric stenosis (IHPS) is the most common inherited form of gastrointestinal obstruction in infancy with a striking male preponderance. Infants present with vomiting due to gastric outlet obstruction caused by hypertrophy of the smooth muscle of the pylorus. Two loci specific to extended pedigrees displaying autosomal dominant inheritance have been identified. A genome scan identified loci on chromosomes 11q14-q22 and Xq23-q24 which are predicted to be responsible for a subset of smaller families with IHPS demonstrating non-Mendelian inheritance. The two linked chromosomal regions both harbour functional candidate genes which are members of the canonical transient receptor potential (TRPC) family of ion channels. Both TRPC5 (Xq23-q24) and TRPC6 (11q14-q22) have a potential role in smooth muscle control and hypertrophy. Here, we report suggestive evidence for a third locus on chromosome 3q12-q25 (Zmax = 2.7, p < 0.004), a region which harbours a third TRPC gene, TRPC1. Fine mapping of all three genes using a tagSNP approach and re-sequencing identified a SNP in the promoter region of TRPC6 and a missense variant in exon 4 of TRPC6 which may be putative causal variants.

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“…It is now generally accepted that there is a defect in a gene. Carter and Powell (1954), by tracing the offspring ofparents, one of whom had pyloric stenosis, showed that one son out of 10 and one daughter out of 50 born to such parents, would develop pyloric stenosis. This view is supported by the fact that the present incidence of three to four cases per 1,000 live births is much higher than the incidence recognized before 1900 (Cautley and Dent, 1903), which in turn may be attributable to the high survival rate of infants operated on for this condition (Wood and Smellie, 1951;Gross, 1953;Aird, 1957;Svenson, 1958).…”

mentioning

confidence: 99%