Preimplantation Genetic Diagnosis for a Chinese Family with Autosomal Recessive Meckel-Gruber Syndrome Type 3 (MKS3)

Abstract

Meckel-Gruber syndrome type 3 is an autosomal recessive genetic defect caused by mutations in TMEM67 gene. In our previous study, we have identified a homozygous TMEM67 mutation in a Chinese family exhibiting clinical characteristics of MKS3, which provided a ground for further PGD procedure. Here we report the development and the first clinical application of the PGD for this MKS3 family. Molecular analysis protocol for clinical PGD procedure was established using 50 single cells in pre-clinical set-up. After whole genomic amplification by multiple displacement amplification with the DNA from single cells, three techniques were applied simultaneously to increase the accuracy and reliability of genetic diagnosis in single blastomere, including real-time PCR with Taq Man-MGB probe, haplotype analysis with polymorphic STR markers and Sanger sequencing. In the clinical PGD cycle, nine embryos at cleavage-stage were biopsied and subjected to genetic diagnosis. Two embryos diagnosed as free of TMEM67 mutation were transferred and one achieving normal pregnancy. Non-invasive prenatal assessment of trisomy 13, 18 and 21 by multiplex DNA sequencing at 18 weeks’ gestation excluded the aneuploidy of the analyzed chromosomes. A healthy boy was delivered by cesarean section at 39 weeks’ gestation. DNA sequencing from his cord blood confirmed the result of genetic analysis in the PGD cycle. The protocol developed in this study was proved to be rapid and safe for the detection of monogenic mutations in clinical PGD cycle.

The Case of Recurrent Lethal Fetal Syndrome: Meckel–Gruber Syndrome

“…Preimplantation genetic diagnosis is another option that has recently been used for primary prevention of MGS. 10 However, to make use of PGD, it is important to first identify the locus of the gene mutation at the DNA level in the index case. Also, it is a costly option and not readily available in low-resource settings.…”

“…Because of the condition being incompatible with life, patient opted for discontinuation of pregnancy and consent for a 2nd trimester medical termination of pregnancy using mifepristone-misoprostol regimen was sought. The aborted fetus weighed 60 gm, and a defect in the occipital bone with outpouching of JSAFOG CASE REPORT 10.5005/jp-journals-10006-1495…”

Diagnosis of Meckel Gruber Syndrome Ultrasound Scan

“…Gruber also published reports of patients with Meckel-Gruber syndrome in 1934 and gave it the name dysencephalia splanchnocystica. Meckel-Gruber syndrome (OMIM 24900) is a lethal, rare, autosomal recessive condition mapped to 6 different loci in chromosomes 17q21-24 (MKS1), 11q13 (MKS2), 8q21.3-q22.1 (MKS3), [4][5] 12q21.31-q21.33 (MKS4), [6] 16q12.2 (MKS5), [7] and 4p15.3 (MKS6) [8]. This mapping suggests genetic heterogeneity in Meckel-Gruber syndrome.…”

The digital epidemiology of dysencephalia splanchnocystica, AKA meckel–gruber syndrome: Retrospective analysis and geographic mapping via google trends

“…Johann Friedrich the formation of pathologic encystations. [1][2][3] Meckel-Gruber syndrome is a rare fatal autosomal recessive condition that exists more frequently in populations where high consanguinity occurs, and it is mapped to at least twelve different loci in different chromosomes. [1][2][3][4][5][6] Hence, MGS represents a genetic heterogeneity.…”

“…[1][2][3] Meckel-Gruber syndrome is a rare fatal autosomal recessive condition that exists more frequently in populations where high consanguinity occurs, and it is mapped to at least twelve different loci in different chromosomes. [1][2][3][4][5][6] Hence, MGS represents a genetic heterogeneity. [1][2][3][4][5][6] The triad of enlarged polycystic kidneys, occipital Encephalocele, and postaxial polydactyly are characteristic for the syndrome.…”