Meier-Gorlin syndrome genotype-phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis

Abstract

Meier-Gorlin syndrome (MGS) is an autosomal recessive disorder characterized by microtia, patellar aplasia/hypoplasia, and short stature. Recently, mutations in five genes from the pre-replication complex (ORC1, ORC4, ORC6, CDT1, and CDC6), crucial in cell-cycle progression and growth, were identified in individuals with MGS. Here, we report on genotype-phenotype studies in 45 individuals with MGS (27 females, 18 males; age 3 months-47 years). Thirty-five individuals had biallelic mutations in one of the five causative pre-replication genes. No homozygous or compound heterozygous null mutations were detected. In 10 individuals, no definitive molecular diagnosis was made. The triad of microtia, absent/hypoplastic patellae, and short stature was observed in 82% of individuals with MGS. Additional frequent clinical features were mammary hypoplasia (100%) and abnormal genitalia (42%; predominantly cryptorchidism and hypoplastic labia minora/majora). One individual with ORC1 mutations only had short stature, emphasizing the highly variable clinical spectrum of MGS. Individuals with ORC1 mutations had significantly shorter stature and smaller head circumferences than individuals from other gene categories. Furthermore, compared with homozygous missense mutations, compound heterozygous mutations appeared to have a more severe effect on phenotype, causing more severe growth retardation in ORC4 and more frequently pulmonary emphysema in CDT1. A lethal phenotype was seen in four individuals with compound heterozygous ORC1 and CDT1 mutations. No other clear genotype-phenotype association was observed. Growth hormone and estrogen treatment may be of some benefit, respectively, to growth retardation and breast hypoplasia, though further studies in this patient group are needed.

Figure 1

Facial features of individuals with Meier–Gorlin syndrome. Frontal and lateral view of 10 individuals with Meier–Gorlin syndrome. Note the different grades of microtia and the microstomia with full lips at young age. In the older individuals, the nose is more prominent and narrow, with a convex profile. Individuals (a) and (b) have mutations in ORC1 (individuals P3 and P4, Table 2); individual (c) has mutations in ORC4 (individual P5, Table 2); individual (d) has mutations in CDT1 (individual P11, Table 2); individual E has mutations in CDC6 (individual P18, Table 2); individuals (f, g, and h) are new individuals with mutations in ORC6 (individuals I2-I4, Table 2). In individuals (i and j), no definitive molecular diagnosis could be made. Individual (j) was previously described by Bongers et al in 2001.

Figure 2

(a) Comparison of height (SD) of individuals with Meier–Gorlin syndrome per gene category in 33 individuals with biallelic mutations and 9 individuals without definitive molecular diagnosis: n=9 ORC1; n=7 ORC4; n=7 ORC6; n=9 CDT1; n=1 CDC6; n=9 no definitive molecular diagnosis. (b) Comparison of head circumference (SD) of individuals with Meier–Gorlin syndrome per gene category 29 individuals with biallelic mutations and 10 individuals without definitive molecular diagnosis: n=8 ORC1; n=5 ORC4; n=6 ORC6; n=9 CDT1; n=1 CDC6; n=10 no definitive molecular diagnosis.