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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).

Record type: Article


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.

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Accepted/In Press date: 15 February 2012
Published date: May 2012
Organisations: Human Development & Health


Local EPrints ID: 334316
ISSN: 1018-4813
PURE UUID: df7e08e5-9dee-41fe-9910-2913ed8f1984

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Date deposited: 06 Mar 2012 17:10
Last modified: 18 Jul 2017 06:11

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Author: Sonja A. de Munnik
Author: Louise S. Bicknell
Author: Salim Aftimos
Author: Jumana Y. Al-Aama
Author: Yolande van Bever
Author: Michael B. Bober
Author: Jill Clayton-Smith
Author: Alaa Y. Edrees
Author: Murray Feingold
Author: Alan Fryer
Author: Johanna M. van Hagen
Author: Raoul C. Hennekam
Author: Maaike C.E. Jansweijer
Author: Diana Johnson
Author: Sarina G. Kant
Author: John M. Opitz
Author: A. Radha Ramadevi
Author: Willie Reardon
Author: Alison Ross
Author: Pierre Sarda
Author: Constance T.R.M. Schrander-Stumpel
Author: Jeroen Schoots
Author: I Karen Temple
Author: Paulien A. Terhal
Author: Annick Toutain
Author: Carol A. Wise
Author: Michael Wright
Author: David L. Skidmore
Author: Mark E. Samuels
Author: Lies H. Hoefsloot
Author: Nine V.A.M. Knoers
Author: Han G. Brunner
Author: Andrew P. Jackson
Author: Ernie M.H. F. Bongers

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