A five-generation family with sacral agenesis and spina bifida: Possible similarities with the mouse T-locus



In man, a malformation that recalls some of the defects associated with T/t mutants in the mouse is sacral agenesis. We report on a family with a high incidence of sacral malformation, ranging from a complete absence of the sacrum (SA), with or without spina bifida aperta, to a spina bifida occulta (SBO) that could only be detected by x-ray. The condition appeared in a man with four children who were all affected, and thereafter, to varying degrees, in 17 of his 28 descendants.

Segregation analysis has been performed in this family, using the Elston and Stewart transmission probability model [1971]. The two traits (SA and SBO) were first studied separately and then together. A fully penetrant major dominant gene is shown to cause SA. When the phenotypes SA and SBO are considered together, Mendelian transmission is rejected. This could be explained genetically by two alternative hypotheses: genetic heterogeneity or a dominant major gene transmitted in excess by heterozygotes (τAa A = 0.896), suggesting a segregation distortion property of an allele at a T-like locus.

In the mouse, the T-locus is linked to the major histocompatibility complex H-2. Thus linkage was investigated between this assumed major SA gene and five polymorphic markers, especially those located on chromosome 6 (PGM3 and HLA). When SA is studied, none of the lod scores are significant. However, when SA + SBO are examined together a high lod score is obtained with PGM3 under the hypothesis of no sporadic cases (lod score = 1.85 at a recombination fraction of 0.087 ± 0.084).

Although similarities with a T-locus (segregarion distortion, possible linkage with PGM3) appear in this pedigree, genetic heterogeneity of SA cannot be excluded.