Mutations in the pre-replication complex cause Meier-Gorlin syndrome

Bicknell, Louise S.; Bongers, Ernie M.H.F.; Leitch, Andrea; Brown, Stephen; Schoots, Jeroen; Harley, Margaret E.; Aftimos, Salim; Al‐Aama, Jumana Y.; Bober, Michael B.; Brown, Paul A.; Bokhoven, Hans van; Dean, John; Edrees, Alaa Y; Feingold, Murray; Fryer, Alan; Hoefsloot, Lies H.; Kau, Nikolaus; Knoers, Nine V A M; MacKenzie, J. M.; Opitz, John M.; Sarda, Pierre; Ross, Alison; Temple, I. Karen; Toutain, Annick; Wise, Carol A.; Wright, Michael J.; Jackson, Andrew P.

doi:10.1038/ng.775

Cited by 223 publications

(274 citation statements)

References 18 publications

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“…[13][14][15] Our clinical data of the 35 individuals with MGS show that all individuals but one had at least two of the three main classical characteristics (microtia, absent/hypoplastic patellae, and short stature). In the one individual with short stature only, it is questionable whether the diagnosis MGS could be made solely on a clinical basis, indicating a broader range of phenotypes in MGS than previously expected.…”

Section: Discussionmentioning

confidence: 79%

“…[2][3][4][5]8,11,[13][14][15][16][17]21 The remaining 10 individuals were not yet described in literature. These 10 individuals were referred to the Human Genetics departments of the Radboud University Nijmegen Medical Centre, the Netherlands and the Western General Hospital in Edinburgh, UK for molecular analysis from the Netherlands, the UK, Ireland and India.…”

Section: Methods Patientsmentioning

confidence: 99%

“…[13][14][15] Copy number variation analysis of ORC4 was performed in eight individuals. 15 In the individual with monoallelic mutations in ORC1, DNA was screened for intragenic deletions/duplications of ORC1, using Multiplex Ligation-dependent Probe Amplification.…”

Section: Molecular Datamentioning

confidence: 99%

“…The patellae of the monozygotic twins with homozygous missense mutations in ORC4 were reported to be palpable in early childhood, but were not palpable at several examinations during adolescence. 14,15 However, in both twins, no radiological examinations were performed.…”

Section: The Classical Triad Of Clinical Featuresmentioning

confidence: 99%

“…IUGR was present in all ten individuals without definitive molecular diagnosis. Table 2); 14 individual E has mutations in CDC6 (individual P18, Table 2); 14 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.…”

Section: Growth and Growth Hormone Treatmentmentioning

confidence: 99%

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

et al. 2012

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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. (MIM 224690) is a form of primordial dwarfism, characterized by microtia, short stature, and absent or hypoplastic patellae. Furthermore, pulmonary emphysema, feeding problems, various skeletal abnormalities, genitourinary anomalies, and mammary hypoplasia frequently accompany this autosomal recessive disorder. Characteristic facial features, which gradually change with age, are frequently described. Infants typically have a small mouth with full lips and micrognathia, whereas in adults, a high forehead and a more prominent, narrow nose with a broad nasal bridge are distinguishable.The first patient was reported by Meier in 1959. 1 Gorlin reported the second patient with a similar phenotype. 2 In total, only 53 cases have been described in the literature thus far. Recently, mutations in ORC1, a pre-replication complex member gene, were identified in 5 out of 204 individuals with microcephalic primordial dwarfism. 13 As individuals with mutations in ORC1 showed overlapping features with MGS, mutation analysis of ORC1 was performed in 33 individuals with MGS and revealed mutations in 4 individuals from three families. 13 Mutation analysis of other genes of this prereplication complex showed mutations in ORC4, ORC6, CDT1, and CDC6 in 14 individuals fro...

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Section: Discussionmentioning

confidence: 79%

Section: Methods Patientsmentioning

confidence: 99%

Section: Molecular Datamentioning

confidence: 99%

Section: The Classical Triad Of Clinical Featuresmentioning

confidence: 99%

Section: Growth and Growth Hormone Treatmentmentioning

confidence: 99%

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

et al. 2012

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Growth in individuals with Majewski osteodysplastic primordial dwarfism type II caused by pericentrin mutations

Bober

Niiler

Duker

et al. 2012

American J of Med Genetics Pt A

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Microcephalic primordial dwarfism (MPD) is a class of disorders characterized by intrauterine growth restriction (IUGR), impaired postnatal growth and microcephaly. Majewski osteodysplastic primordial dwarfism type II (MOPD II) is one of the more common conditions within this group. MOPD II is caused by truncating mutations in pericentrin (PCNT) and is inherited in an autosomal recessive manner. Detailed growth curves for length, weight, and OFC are presented here and derived from retrospective data from 26 individuals with MOPD II confirmed by molecular or functional studies. Severe pre-and postnatal growth failure is evident in MOPD II patients. The length, weight, and OFC at term (when corrected for gestational age) were À7.0, À3.9, and À4.6 standard deviation (SD) below the population mean and equivalent to the 50th centile of a 28-29-, 31-32-, and 30-31-week neonate, respectively. While at skeletal maturity, the height, weight, and OFC were À10.3, À14.3, and À8.5 SD below the population mean and equivalent to the size of 3-year 10-to 11-month-old, a 5-year 2-to 3-month-old, and 5-to 6-month-old, respectively. During childhood, MOPD II patients grow with slowed, but fairly constant growth velocities and show no evidence of any pubertal growth spurt. Treatment with human growth hormone (n ¼ 11) did not lead to any significant improvement in final stature. The growth charts presented here will be of assistance with diagnosis and management of MOPD II, and should have particular utility in nutritional management of MOPD II during infancy.

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Meier–Gorlin syndrome: Growth and secondary sexual development of a microcephalic primordial dwarfism disorder

Munnik

Otten

Schoots

et al. 2012

American J of Med Genetics Pt A

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Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recently, mutations in the ORC1, ORC4, ORC6, CDT1, and CDC6 genes, encoding components of the pre-replication complex, have been identified. This complex is essential for DNA replication and therefore mutations are expected to impair cell proliferation and consequently could globally reduce growth. However, detailed growth characteristics of MGS patients have not been reported, and so this is addressed here through study of 45 MGS patients, the largest cohort worldwide. Here, we report that growth velocity (length) is impaired in MGS during pregnancy and first year of life, but, thereafter, height increases in paralleled normal reference centiles, resulting in a mean adult height of À4.5 standard deviations (SD). Height is dependent on ethnic background and underlying molecular cause, with ORC1 and ORC4 mutations causing more severe short stature and microcephaly. Growth hormone therapy (n ¼ 9) was generally ineffective, though in two patients with significantly reduced IGF1 levels, growth was substantially improved by GH treatment, with 2SD and 3.8 SD improvement in height. Growth parameters for monitoring growth in future MGS patients are provided and as well we highlight that growth is disproportionately affected in certain structures, with growth related minor genital abnormalities (42%) and mammary hypoplasia (100%) frequently present, in addition to established effects on ears and patellar growth.

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Mutations in the pre-replication complex cause Meier-Gorlin syndrome

Cited by 223 publications

References 18 publications

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

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

Growth in individuals with Majewski osteodysplastic primordial dwarfism type II caused by pericentrin mutations

Meier–Gorlin syndrome: Growth and secondary sexual development of a microcephalic primordial dwarfism disorder

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