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

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

Research output: Contribution to journalArticle

51 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)598-606
Number of pages9
JournalEuropean Journal of Human Genetics
Volume20
Issue number6
DOIs
StatePublished - Jun 2012

Fingerprint

Genotype
Phenotype
Mutation
Genes
Breast
Growth
Pulmonary Emphysema
Cryptorchidism
Genitalia
Genetic Association Studies
Missense Mutation
Meier-Gorlin syndrome
Growth Hormone
Cell Cycle
Estrogens
Head
Congenital Microtia
Therapeutics

Keywords

  • ear-patella-short stature syndrome
  • genotype-phenotype
  • Meier-Gorlin syndrome
  • origin recognition complex
  • pre-replication complex

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

De Munnik, S. A., Bicknell, L. S., Aftimos, S., Al-Aama, J. Y., Van Bever, Y., Bober, M. B., ... Bongers, E. 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), 598-606. https://doi.org/10.1038/ejhg.2011.269

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.; Bongers, Ernie M H F.

In: European Journal of Human Genetics, Vol. 20, No. 6, 06.2012, p. 598-606.

Research output: Contribution to journalArticle

De Munnik, SA, Bicknell, LS, Aftimos, S, Al-Aama, JY, Van Bever, Y, Bober, MB, Clayton-Smith, J, Edrees, AY, Feingold, M, Fryer, A, Van Hagen, JM, Hennekam, RC, Jansweijer, MCE, Johnson, D, Kant, SG, Opitz, JM, Ramadevi, AR, Reardon, W, Ross, A, Sarda, P, Schrander-Stumpel, CTRM, Schoots, J, Temple, IK, Terhal, PA, Toutain, A, Wise, CA, Wright, M, Skidmore, DL, Samuels, ME, Hoefsloot, LH, Knoers, NVAM, Brunner, HG, Jackson, AP & Bongers, EMHF 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, vol. 20, no. 6, pp. 598-606. https://doi.org/10.1038/ejhg.2011.269
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. ; Bongers, Ernie M H F. / Meier-Gorlin syndrome genotype-phenotype studies : 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis. In: European Journal of Human Genetics. 2012 ; Vol. 20, No. 6. pp. 598-606.
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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.",
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AU - De Munnik, Sonja A.

AU - Bicknell, Louise S.

AU - Aftimos, Salim

AU - Al-Aama, Jumana Y.

AU - Van Bever, Yolande

AU - Bober, Michael B.

AU - Clayton-Smith, Jill

AU - Edrees, Alaa Y.

AU - Feingold, Murray

AU - Fryer, Alan

AU - Van Hagen, Johanna M.

AU - Hennekam, Raoul C.

AU - Jansweijer, Maaike C E

AU - Johnson, Diana

AU - Kant, Sarina G.

AU - Opitz, John M.

AU - Ramadevi, A. Radha

AU - Reardon, Willie

AU - Ross, Alison

AU - Sarda, Pierre

AU - Schrander-Stumpel, Constance T R M

AU - Schoots, Jeroen

AU - Temple, I. Karen

AU - Terhal, Paulien A.

AU - Toutain, Annick

AU - Wise, Carol A.

AU - Wright, Michael

AU - Skidmore, David L.

AU - Samuels, Mark E.

AU - Hoefsloot, Lies H.

AU - Knoers, Nine V A M

AU - Brunner, Han G.

AU - Jackson, Andrew P.

AU - Bongers, Ernie M H F

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KW - Meier-Gorlin syndrome

KW - origin recognition complex

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