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

de Munnik, Sonja A., Bicknell, Louise S., Aftimos, Salim, Al-Aama, Jumana Y., van Bever, Yolande, Bober, Michael B., Clayton-Smith, Jill, Edrees, Alaa Y., Feingold, Murray, Fryer, Alan, van Hagen, Johanna M., Hennekam, Raoul C., Jansweijer, Maaike C.E., Johnson, Diana, Kant, Sarina G., Opitz, John M., Ramadevi, A. Radha, Reardon, Willie, Ross, Alison, Sarda, Pierre, Schrander-Stumpel, Constance T.R.M., Schoots, Jeroen, Temple, I Karen, Terhal, Paulien A., Toutain, Annick, Wise, Carol A., Wright, Michael, Skidmore, David L., Samuels, Mark E., Hoefsloot, Lies H., Knoers, Nine V.A.M., Brunner, Han G., Jackson, Andrew P. and Bongers, Ernie M.H. F. (2012) Meier–Gorlin syndrome genotype–phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis European Journal of Human Genetics, 20, (6), pp. 598-606. (doi:10.1038/ejhg.2011.269).


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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.

Item Type: Article
Digital Object Identifier (DOI): doi:10.1038/ejhg.2011.269
ISSNs: 1018-4813 (print)
Related URLs:
Organisations: Human Development & Health
ePrint ID: 334316
Date :
Date Event
15 February 2012Accepted/In Press
May 2012Published
Date Deposited: 06 Mar 2012 17:10
Last Modified: 17 Apr 2017 17:27
Further Information:Google Scholar

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