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Case Reports
. 2022 Aug 17;23(16):9234.
doi: 10.3390/ijms23169234.

Meier-Gorlin Syndrome: Clinical Misdiagnosis, Genetic Testing and Functional Analysis of ORC6 Mutations and the Development of a Prenatal Test

Maria S Nazarenko  1   2 , Iuliia V Viakhireva  3 , Mikhail Y Skoblov  3 , Elena V Soloveva  1 , Aleksei A Sleptcov  1 , Ludmila P Nazarenko  1   2
Affiliations
Case Reports

Meier-Gorlin Syndrome: Clinical Misdiagnosis, Genetic Testing and Functional Analysis of ORC6 Mutations and the Development of a Prenatal Test

Maria S Nazarenko et al. Int J Mol Sci. .

Abstract

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 ORC6 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 ORC6 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 ORC6 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.

Keywords: Jeune syndrome; Meier–Gorlin syndrome; ORC6; exon skipping variant; prenatal genetic testing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The case of Meier–Gorlin syndrome. (A) The pedigree of the proband; (B) the phenotype of the proband; (C) molecular genetic testing of the patient by clinical exome sequencing; (D) Sanger sequencing validation of the variants and of their inheritance from the parents.
Figure 2
Figure 2
In vitro minigene analysis of c.449+5G>A of the ORC6 gene. (A) The scheme of plasmid construction for the minigene assay; (B) an agarose gel image from RT-PCR analysis of chimeric transcripts; (C) results of Sanger sequencing of splicing products in minigenes.
Figure 3
Figure 3
The prenatal genetic diagnostic system for c.2T>C(p.Met1Thr) and c.449+5G>A of the ORC6 gene. (A,B) PCR-RFLP and PAGE analyses; (C) PCR and fragment analysis of AGAT repeats of exon 7. Lane L: pUC19/MspI Ladder; lane ‘PCR’: the undigested amplicon; lane H: an unrelated healthy control; lane C: the affected child; lane F: father; and lane M: mother.
Figure 4
Figure 4
The ORC6 gene and protein and phenotypes of mutations [2,4,5].
See this image and copyright information in PMC

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