Meier–Gorlin Syndrome: Clinical Misdiagnosis, Genetic Testing and Functional Analysis of <i>ORC6</i> Mutations and the Development of a Prenatal Test
Meier–Gorlin syndrome (MGS) is a rare genetic developmental disorder that causes primordial proportional dwarfism, microtia, the absence of or hypoplastic patellae and other skeletal anomalies. Skeletal symptoms overlapping with other syndromes make MGS difficult to diagnose clinically. We describe...
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MDPI AG
2022-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/16/9234 |
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| author | Maria S. Nazarenko Iuliia V. Viakhireva Mikhail Y. Skoblov Elena V. Soloveva Aleksei A. Sleptcov Ludmila P. Nazarenko |
| author_facet | Maria S. Nazarenko Iuliia V. Viakhireva Mikhail Y. Skoblov Elena V. Soloveva Aleksei A. Sleptcov Ludmila P. Nazarenko |
| author_sort | Maria S. Nazarenko |
| collection | DOAJ |
| description | Meier–Gorlin syndrome (MGS) is a rare genetic developmental disorder that causes primordial proportional dwarfism, microtia, the absence of or hypoplastic patellae and other skeletal anomalies. Skeletal symptoms overlapping with other syndromes make MGS difficult to diagnose clinically. We describe a 3-year-old boy with short stature, recurrent respiratory infections, short-rib dysplasia, tower head and facial dysmorphisms who was admitted to the Tomsk Genetic Clinic to verify a clinical diagnosis of Jeune syndrome. Clinical exome sequencing revealed two variants (compound heterozygosity) in the <i>ORC6</i> gene: c.2T>C(p.Met1Thr) and c.449+5G>A. In silico analysis showed the pathogenicity of these two mutations and predicted a decrease in donor splicing site strength for c.449+5G>A. An in vitro minigene assay indicated that variant c.449+5G>A causes complete skipping of exon 4 in the <i>ORC6</i> gene. The parents requested urgent prenatal testing for MGS for the next pregnancy, but it ended in a miscarriage. Our results may help prevent MGS misdiagnosis in the future. We also performed in silico and functional analyses of <i>ORC6</i> mutations and developed a restriction fragment length polymorphism and haplotype-based short-tandem-repeat assay for prenatal genetic testing for MGS. These findings should elucidate MGS etiology and improve the quality of genetic counselling for affected families. |
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| language | English |
| last_indexed | 2024-03-09T04:19:20Z |
| publishDate | 2022-08-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-bf71e556054a4676aace7010453f75a72023-12-03T13:49:18ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-08-012316923410.3390/ijms23169234Meier–Gorlin Syndrome: Clinical Misdiagnosis, Genetic Testing and Functional Analysis of <i>ORC6</i> Mutations and the Development of a Prenatal TestMaria S. Nazarenko0Iuliia V. Viakhireva1Mikhail Y. Skoblov2Elena V. Soloveva3Aleksei A. Sleptcov4Ludmila P. Nazarenko5Research Institute of Medical Genetics, Tomsk National Research Medical Center, Russian Academy of Sciences, 634050 Tomsk, RussiaResearch Centre for Medical Genetics, 115522 Moscow, RussiaResearch Centre for Medical Genetics, 115522 Moscow, RussiaResearch Institute of Medical Genetics, Tomsk National Research Medical Center, Russian Academy of Sciences, 634050 Tomsk, RussiaResearch Institute of Medical Genetics, Tomsk National Research Medical Center, Russian Academy of Sciences, 634050 Tomsk, RussiaResearch Institute of Medical Genetics, Tomsk National Research Medical Center, Russian Academy of Sciences, 634050 Tomsk, RussiaMeier–Gorlin syndrome (MGS) is a rare genetic developmental disorder that causes primordial proportional dwarfism, microtia, the absence of or hypoplastic patellae and other skeletal anomalies. Skeletal symptoms overlapping with other syndromes make MGS difficult to diagnose clinically. We describe a 3-year-old boy with short stature, recurrent respiratory infections, short-rib dysplasia, tower head and facial dysmorphisms who was admitted to the Tomsk Genetic Clinic to verify a clinical diagnosis of Jeune syndrome. Clinical exome sequencing revealed two variants (compound heterozygosity) in the <i>ORC6</i> gene: c.2T>C(p.Met1Thr) and c.449+5G>A. In silico analysis showed the pathogenicity of these two mutations and predicted a decrease in donor splicing site strength for c.449+5G>A. An in vitro minigene assay indicated that variant c.449+5G>A causes complete skipping of exon 4 in the <i>ORC6</i> gene. The parents requested urgent prenatal testing for MGS for the next pregnancy, but it ended in a miscarriage. Our results may help prevent MGS misdiagnosis in the future. We also performed in silico and functional analyses of <i>ORC6</i> mutations and developed a restriction fragment length polymorphism and haplotype-based short-tandem-repeat assay for prenatal genetic testing for MGS. These findings should elucidate MGS etiology and improve the quality of genetic counselling for affected families.https://www.mdpi.com/1422-0067/23/16/9234Meier–Gorlin syndromeJeune syndrome<i>ORC6</i>exon skipping variantprenatal genetic testing |
| spellingShingle | Maria S. Nazarenko Iuliia V. Viakhireva Mikhail Y. Skoblov Elena V. Soloveva Aleksei A. Sleptcov Ludmila P. Nazarenko Meier–Gorlin Syndrome: Clinical Misdiagnosis, Genetic Testing and Functional Analysis of <i>ORC6</i> Mutations and the Development of a Prenatal Test International Journal of Molecular Sciences Meier–Gorlin syndrome Jeune syndrome <i>ORC6</i> exon skipping variant prenatal genetic testing |
| title | Meier–Gorlin Syndrome: Clinical Misdiagnosis, Genetic Testing and Functional Analysis of <i>ORC6</i> Mutations and the Development of a Prenatal Test |
| title_full | Meier–Gorlin Syndrome: Clinical Misdiagnosis, Genetic Testing and Functional Analysis of <i>ORC6</i> Mutations and the Development of a Prenatal Test |
| title_fullStr | Meier–Gorlin Syndrome: Clinical Misdiagnosis, Genetic Testing and Functional Analysis of <i>ORC6</i> Mutations and the Development of a Prenatal Test |
| title_full_unstemmed | Meier–Gorlin Syndrome: Clinical Misdiagnosis, Genetic Testing and Functional Analysis of <i>ORC6</i> Mutations and the Development of a Prenatal Test |
| title_short | Meier–Gorlin Syndrome: Clinical Misdiagnosis, Genetic Testing and Functional Analysis of <i>ORC6</i> Mutations and the Development of a Prenatal Test |
| title_sort | meier gorlin syndrome clinical misdiagnosis genetic testing and functional analysis of i orc6 i mutations and the development of a prenatal test |
| topic | Meier–Gorlin syndrome Jeune syndrome <i>ORC6</i> exon skipping variant prenatal genetic testing |
| url | https://www.mdpi.com/1422-0067/23/16/9234 |
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