Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension

James E. Loyd, Merlin C. Butler, Tatiana M. Foroud, P. Michael Conneally, John A. Phillips, John H. Newman

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189 Scopus citations


The genetic basis of familial primary pulmonary hypertension (FPPH) is unknown, but the clinical and pathologic features are the same as in sporadically occurring primary pulmonary hypertension (PPH). Because few families with this disease have been reported, the mode of inheritance and genetic features have not been dearly established. We previously reported a tendency for decreasing age of onset in subsequent generations of affected families. The purpose of this study was to examine the pattern of inheritance in a large number of families in an attempt to find clues to pathogenesis. From 24 families we studied 429 members, 124 of whom were known to carry the gene for disease. We constructed cumulative mortality curves for each gender of the 99 affected individuals. We analyzed gender ratios of progeny of affected members and carriers and compared age at death of affected members by generation. More females (160) than males (122) were born to persons carrying the gene, p < 0.01, suggesting selective wastage of male fetuses or an abnormal primary sex ratio. Genetic anticipation was confirmed; the age at death was 45.6 ± 14.5 versus 36.3 ± 12.6 versus 24.2 ± 11 standard deviation (SD) years in successive generations, p < 0.05. Five cases of male- to-male transmission were observed, excluding X-linkage. Age at death was the same for males and females. More females had the gene (84 females, 40 males) and more females with the gene developed disease (72 of 84 females [86%] versus 27 of 40 males [68%]). The disease has highly variable penetrance among families. Genetic anticipation suggests that trinucleotide repeat amplification is the mechanism for the molecular basis for disease, similar to fragile X syndrome, myotonic dystrophy, and Huntington's disease. Abnormal gender ratio of progeny raises the possibility that the gene is involved in embryologic development. These clues provide direction for a search for the gene responsible for FPPH.

Original languageEnglish (US)
Pages (from-to)93-97
Number of pages5
JournalAmerican journal of respiratory and critical care medicine
Issue number1
StatePublished - Jul 1995

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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