Case Report: Preimplantation Genetic Testing for Meckel Syndrome Induced by Novel Compound Heterozygous Mutations of MKS1

Lin, Tao; Ma, Yanlin; Zhou, Danni; Sun, Liwei; Chen, Ke; Xiang, Yezhou; Tong, Keya; Jia, Chaoli; Jiang, Kean; Liu, Dongyun; Huang, Gangliang

doi:10.3389/fgene.2022.843931

Cited by 3 publications

(3 citation statements)

References 32 publications

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“…After confirming the pathogenicity of the genetic variant, the couple was offered genetic counseling, which provided strong evidence for the selection of reproductive options and the subsequent prenatal diagnoses, and in the end, the couple selected PGT‐M to block inheritance of the pathogenic gene. PGT‐M has been previously used to block inheritance of pathogenic genes causing MKS1 (Lin et al., 2022) and MKS5 (Zhang et al., 2022).…”

Section: Discussionmentioning

confidence: 99%

Novel homozygous mutations in TXNDC15 causing Meckel syndrome

Deng,

Xie

2023

Molec Gen & Gen Med

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BackgroundMeckel syndrome (MKS) is the most severe form of an autosomal recessive ciliopathy and is clinically characterized by occipital encephalocele, severely polycystic kidneys, and postaxial polydactyly (toes). The association of TXNDC15‐related MKS has been reported. We report the case of a homozygous mutation in the TXNDC15 gene, causing MKS14 in the Chinese population.MethodsThe fetal skin tissue and parental peripheral blood were retained for whole‐exome sequencing and Sanger sequencing, which investigated the potential pathogenic variants associated with MKS.ResultsThe fetus was homozygous for a mutation in the TXNDC15 gene (NM_024715.3), specifically c.560delA (p.Asn187llefsTer4), and both parents were heterozygous for this mutation.ConclusionOur study identified a new mutation that adds to the mutational landscape of MKS, which provide a basis for genetic counseling and the selection of reproductive options.

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Section: Discussionmentioning

confidence: 99%

Novel homozygous mutations in TXNDC15 causing Meckel syndrome

Deng,

Xie

2023

Molec Gen & Gen Med

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“…It has been documented that in some cases, multiple allelism at a single locus or within a single gene can account for some of this phenotypic variability (Chang et al, 2006;Chen, 2007). Recently novel compound variants have been reported in CEP290 (Peng et al, 1935), and aggregating results regarding mutations in MKS1 have resulted in a proposed genotype-phenotype correlation linking the severity of mutations and the domains affected to diagnoses of either MKS, JBTS or BBS (Leitch et al, 2008;Luo et al, 2020; Frontiers in Genetics frontiersin.org Lin et al, 2022). Further studies are needed to not only understand the genotype-phenotype correlation in ciliopathies but also formulate efficient genetic testing so that counseling can be provided to families predisposed to developing debilitating ciliopathies.…”

Section: Discussionmentioning

confidence: 99%

Prenatal phenotype analysis and mutation identification of a fetus with meckel gruber syndrome

et al. 2022

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Ciliopathies are a class of inherited severe human disorders that occur due to defective formation or function of cilia. The RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting protein1-like) gene encodes for a ciliary protein involved in regulating cilia formation and function. Mutations in RPGRIP1L cause ciliopathies associated with severe embryonic defects, such as Meckel-Gruber Syndrome (MKS). Here we report RPGRIP1L mutation analysis in a family diagnosed with MKS. The clinical manifestations of the fetus included thoraco-lumbar open neural tube defect with associated Chiari type II malformation and hydrocephalus, bilateral club feet, and single right kidney/ureter. Analysis of the parental DNA samples revealed that the father carried a previously reported mutation R1236C/+ whereas the mother had a novel splice site mutation IVS6+1 G > A/+ in RPGRIP1L. The splice site mutation resulted in the exclusion of in-frame exon 6 of RPGRIP1L (RPGRIP1L-∆Ex6) but expressed a stable protein in fibroblasts derived from the parents’ skin biopsies. The GFP-RPGRIP1L-∆Ex6 mutant protein exhibited relatively reduced ciliary localization in transiently-transfected cultured RPE-1 cells. Taken together, this study identifies a novel RPGRIP1L variant RPGRIP1L-∆Ex6, which in combination with RPGRIP1L-R1236C is associated with MKS. We also suggest that the deletion of exon 6 of RPGRIP1L leads to reduced ciliary localization of RPGRIP1L, indicating a plausible mechanism of associated disease.

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“…Meckel Syndrome (MKS, OMIM #249000) is a rare and fatal autosomal recessive ciliopathy with an incidence ranging from 1:13,250 to 1:140,000 ( Young et al, 1985 ; Yaqoubi and Fatema, 2018 ; Lin et al, 2022 ). MKS is a highly clinically heterogeneous and multisystem disorder characterised by classic features—occipital encephalocele, polycystic kidneys, postaxial polydactyly and other anomalies (including liver fibrosis, central nervous system malformations and genital anomalies) ( Logan et al, 2011 ; Hartill et al, 2017 ; Liu et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of novel TMEM231 gene splice variants and pathological findings in a fetus with Meckel Syndrome

Zhang,

Yang,

Chen

et al. 2023

Front. Genet.

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Background: Meckel Syndrome (MKS, OMIM #249000) is a rare and fatal autosomal recessive ciliopathy with high clinical and genetic heterogeneity. MKS shows complex allelism with other related ciliopathies such as Joubert Syndrome (JBTS, OMIM #213300). In MKS, the formation and function of the primary cilium is defective, resulting in a multisystem disorder including occipital encephalocele, polycystic kidneys, postaxial polydactyly, liver fibrosis, central nervous system malformations and genital anomalies. This study aimed to analyze the genotype of MKS patients and investigate the correlation between genotype and phenotype.Methods: A nonconsanguineous couple who conceived four times with a fetus affected by multiorgan dysfunction and intrauterine fetal death was studied. Whole exome sequencing (WES) was performed in the proband to identify the potentially pathogenic variant. Sanger sequencing was performed in family members. In silico tools were used to analyse the pathogenicity of the identified variants. cDNA TA-cloning sequencing was performed to validate the effects of intronic variants on mRNA splicing. Quantitative real-time PCR was performed to investigate the effect of the variants on gene expression. Immunofluorescence was performed to observe pathological changes of the primary cilium in kidney tissue from the proband.Results: Two splice site variants of TMEM231 (NM_001077418.2, c.583-1G>C and c.583-2_588delinsTCCTCCC) were identified in the proband, and the two variants have not been previously reported. The parents were confirmed as carriers. The two variants were predicted to be pathogenic by in silico tools and were classified as pathogenic/likely pathogenic variants according to the American College of Medical Genetics and Genomics guideline. cDNA TA cloning analysis showed that both splice site variants caused a deletion of exon 5. RT-PCR revealed that the expression of TMEM231 was significantly decreased and immunofluorescence showed that the primary cilium was almost absent in the proband’s kidney tissue.Conclusion: We reported the clinical, genetic, molecular and histochemical characterisation of a family affected by MKS. Our findings not only extended the mutation spectrum of the TMEM231 gene, but also revealed for the first time the pathological aetiology of primary cilia in humans and provide a basis for genetic counselling of the parents to their offspring.

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Case Report: Preimplantation Genetic Testing for Meckel Syndrome Induced by Novel Compound Heterozygous Mutations of MKS1

Cited by 3 publications

References 32 publications

Novel homozygous mutations in TXNDC15 causing Meckel syndrome

Novel homozygous mutations in TXNDC15 causing Meckel syndrome

Prenatal phenotype analysis and mutation identification of a fetus with meckel gruber syndrome

Identification of novel TMEM231 gene splice variants and pathological findings in a fetus with Meckel Syndrome

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