A large-scale mutation search reveals genetic heterogeneity in 3M syndrome

Abstract

The 3M syndrome is a rare autosomal recessive disorder recently ascribed to mutations in the CUL7 gene and characterized by severe pre- and postnatal growth retardation. Studying a series of 33 novel cases of 3M syndrome, we have identified deleterious CUL7 mutations in 23/33 patients, including 19 novel mutations and one paternal isodisomy of chromosome 6 encompassing a CUL7 mutation. Lack of mutations in 10/33 cases and exclusion of the CUL7 locus on chromosome 6p21.1 in six consanguineous families strongly support the genetic heterogeneity of the 3M syndrome.

Figure 1

Facial and skeletal features of patient no. 14 at 3 years of age. (a) Note the round face, frontal bossing, short nose and full lips. (b) Note tall vertebral bodies and the hip dislocation.

Figure 2

Skeletal features of a child at 7 years of age with 3M syndrome and without a CUL7 mutation. Note the long slender tubular bones and tall vertebral bodies.

Figure 3

(a) Foetal case of 3M syndrome. The foetus presented with severe growth retardation, normal head circumference, characteristic facial features, prominent heels and long slender tubular bones suggestive of 3M syndrome. (b) Histological study of the femoral growth plate. Note the increased density and size of chondrocytes in the resting and proliferative zones and the defect in matrix production with no major abnormalities in the prehypertrophic or hypertrophic zones (1: resting zone; 2: proliferative zone; 3: hypertrophic zone).