CRISPR-Cas9-Generated TXNDC15 c.560delA Homozygous Mouse Model Exhibits Meckel-Gruber Syndrome Phenotype.

Atrioventricular canal defect in Bardet-Biedl syndrome: Clinical evidence supporting the link between atrioventricular canal defect and polydactyly syndromes with ciliary dysfunction536

Cilia‐related disorders (ciliopathies) are characterised by great clinical and genetic heterogeneity and overlaps between different disease entities. Meckel syndrome (MKS) is generally allelic to Joubert syndrome and related disorders, and resides at the severe end of the broad phenotypic spectrum of ciliopathies. MKS is a usually autosomal recessive, multisystemic disorder of early developmental rather than degenerative nature. Classic disease manifestations comprise occipital meningoencephalocele, cystic kidneys, hepatobiliary ductal plate malformation and postaxial polydactyly, whereas several other additional features such as heart defects and cleft lip/palate have also been reported. Survival beyond birth or the neonatal period is unusual with the vast majority of cases dying in utero. Until recently and before next‐generation sequencing (NGS) have emerged, molecular genetic testing of MKS and related ciliopathies was considerably hampered by its extensive locus heterogeneity. However, NGS‐based technologies make genetic testing now possible and have revolutionised research and diagnostics. For example, specific disease panels that allow sequencing of all disease genes in parallel significantly improve genetic diagnostics and lead to reduction of turnaround times and costs. Key Concepts: Meckel syndrome (MKS) resides at the severe end of the broad phenotypic spectrum of cilia‐related disorders (ciliopathies). MKS and other ciliopathies are clinically and genetically heterogeneous. MKS is a usually autosomal recessive, early developmental multisystemic disorder. Most patients die in utero, survival beyond birth or the neonatal period is unusual. Classic disease manifestations comprise occipital meningoencephalocele, cystic kidneys, hepatobiliary ductal plate malformation and postaxial polydactyly, but additional features are common. At least 10 genes are known for MKS currently, other ciliary genes are thought to be allelic; that is why more than a dozen genes have to be considered to be disease relevant in patients with MKS. Efficient molecular genetic testing of MKS and related disorders have only become feasible with emerging next‐generation sequencing (NGS)‐based approaches. Specific disease panels (e.g. for MKS and related disorders) allow sequencing of all disease genes in parallel and very efficiently lead to reduction of turnaround times and costs.

Background:
 
 Meckel-Gruber syndrome is categorised under the broad “umbrella” of syndromic ciliopathies. There is a shortage of epidemiological studies surveying the region of the Middle East and Arabic countries.
 
 Materials and methods:
 
 The review of the literature was conducted systematically, from the 1st to the 9th of June 2018, across medical and paramedical electronic databases including PubMed-NCBI, the Cochrane Library, and Elsevier database via predefined Medical Subject Headings (MeSH) terms. The words used included all possible combinations of synonyms for Meckel syndrome, Meckel-Gruber syndrome, Gruber syndrome, Dysencephalia Splanchnocystica, ciliopathies, and syndromic ciliopathies.
 
 Results:
 
 The total number of hits for all databases was 2089963 distributed as 2085668 (NCBI-PubMed), 1052 (The Cochrane Library), and 3243 (Elsevier). The most informative combination of keywords was [(Ciliopathies AND “Meckel syndrome type-1”]. The total number of reference material was restricted to twenty-six. The level-of-evidence of our study is level-2b, by the categorisation scheme adopted by the Oxford Centre for Evidence-based Medicine. Our case report represents the first documented case in literature from Iraq. The diagnosis was based on the history of consanguinity of the parents, prior history of induced abortion of a malformed male fetus, and the diagnostic clinical triad postnatally of occipital encephalocele, post-axial polydactyly, and polycystic kidneys manifested as bilateral abdominal distension primarily affecting the loin.
 
 Conclusion:
 
 Future cases from Iraq should be investigated, via ecological and aggregate analytics, in correlation with chemical and radiological exposure following the American invasion of Iraq.

Contribution of Apoptosis and Apoptosis-Related Proteins to the Malformation of the Primitive Intrahepatic Biliary System in Meckel Syndrome

Meckel Gruber syndrome (MKS) is a lethal, autosomal, recessive, multisystemic disorder, associated with mutations affecting ciliogenesis. Since the time it was first reported; only 200 cases have been reported. From January 2004 to December 2010, we evaluated 268 fetal autopsies in our institute, in the Department of Pathology; two of these fetuses were diagnosed as MKS. MKS is characterized by occipital meningoencephalocele, cystic kidneys, postaxial polydactyly, and fibrosis in the liver. MKS cases show genetic heterogeneity. MKS results in 100% fetal or neonatal mortality. As MKS has a high risk (25%) of recurrence; parents should be counseled for future pregnancies.

Meckel syndrome (MIM 249.000) is an autosomal recessive disorder with a variable spectrum of anomalies. Since the first reports of this syndrome, very broad diagnostic criteria have been proposed, but the process of defining them continues. It is probable that at least two of three manifestations, including cystic kidney dysplasia, occipital encephalocele or other anomaly of the central nervous system, and postaxial polydactyly occur in most cases. Arrest of the development of intrahepatic bile ducts at the stage of the bilaminar plate formation or ductal plate malformation is considered of high diagnostic value in Meckel syndrome, but there is no complete agreement in the literature about its occurrence. The aims of this investigation were to study the prevalence and morphologic patterns of ductal plate malformation of the liver in Meckel syndrome by evaluating the dilatation of primitive biliary structures and the increase in connective tissue of the portal tract. Archival data files from four German centers (Berlin, Freiburg, Heidelberg, Mainz) were reviewed. Liver sections of 30 well-studied fetuses with Meckel syndrome were immunostained with antibodies against cytokeratins (intermediate filaments of the cytoskeleton) and factor VIII (an endothelial cell marker) and were evaluated both qualitatively and quantitatively. Cystic kidney dysplasia, occipital encephalocele, and postaxial polydactyly were found in 100%, 90%, and 83.3% of the fetuses, respectively. Ductal plate malformation of the liver was a constant anomaly in Meckel syndrome, seen as frequently as renal lesions. We observed essentially two kinds of hepatic lesions: 23 cases showed mainly a cystic dilatation of primitive biliary structures with little portal fibrosis, while 7 cases showed mainly rings of interrupted curved lumina around a central fibrovascular axis and pronounced portal fibrosis. In these seven cases an abnormal pattern of the portal vein, with many small and closely spaced branches of the portal vein (the so-called pollard willow pattern), was also seen. With respect to other fetal developmental anomalies, no difference between the two types of lesions was found. We also provide a potentially useful comprehensive review of other genetic syndromes in which ductal plate malformations may occur.

Meckel-Gruber syndrome (MKS) is an autosomal recessive, usually lethal multisystemic disorder characterized by early developmental anomalies of the central nervous system, cystic kidney dysplasia, hepatobiliary ductal plate malformation, and postaxial polydactyly. Three MKS loci have been mapped and recently, two genes were identified: MKS1 on 17q22 in Caucasian kindreds and MKS3 on 8q22 in Omani and Pakistani families, putting MKS on the growing list of ciliary disorders ("ciliopathies"). We performed linkage analysis for MKS1-3 in 14 consanguineous and/or multiplex families of different ethnic origins with histologic diagnosis and at least three classic MKS manifestations in each kindred. Unexpectedly, only five families were linked to any of the known MKS loci, clearly indicating further locus heterogeneity. All five families showed homozygosity for MKS1 and, intriguingly, were of non-Caucasian origin. MKS1 sequencing revealed no mutation in two of these pedigrees, whereas different, novel splicing defects were identified in the three other families and an additional sporadic German patient. Given that all of our mutations and two of the in total four known MKS1 changes cause aberrant splicing (while the other two known mutations were frameshift mutations), we hypothesize that splicing defects are a crucial mutational mechanism in MKS1 which apparently is one of the main loci and key players in MKS. Our results indicate that MKS1 mutations are not restricted to the Caucasian gene pool and suggest further genetic heterogeneity for MKS. Overall, our data have immediate implications for genetic counselling and testing approaches in MKS.

Meckel Syndrome: Genetics, Perinatal Findings, and Differential Diagnosis

ABSTRACT. Introduction: Meckel-Gruber Syndrome was first described by J R Meckel in 1822. It is an autosomal recessive disorder, and is caused by the failure of mesodermal induction. The typical triad of Meckel-Gruber Syndrome (MGS) involves meningo-encephalocele, polycystic kidneys and postaxial polydactyly. The worldwide incidence varies from 1 in 1.300 to 1 in 140.000 live births.Case: In this report, we present a case of MGS in which the diagnosis was made at 19 weeks of gestation based on ultrasonographic findings of the typical triad of the disease (encephalocele, polycystic kidneys, and polydactyly) These features were suggestive of the diagnosis of Meckel Gruber Syndrome (MGS). She had also placenta previa totalis. The patient was counselled regarding the lethal outcome of MGS. Unfortunately, the family did not approve the termination of pregnancy. At the 32nd week, she referred to hospital with complaints of vaginal bleeding and uterine contractions. An emergency cesarean section was perfomed due to plasental malposition. A 1380 gr, female fetus was delivered. First and 5th minute Apgar scores were 1 and 0, respectively. Consequently, the baby died after 45 minutes of neonatal resuscitation.Conclusıon: MGS is a lethal disorder. One cannot speak about survival of the fetus because of the pulmonary hypoplasia. The parents should be counseled about prognosis of the fetus and the outcome. Counselers should strictly give information about the recurrence risk for the next pregnancies.

Dear Sir, We are reporting a case of Meckel-Gruber Syndrome (MGS), which was identified by its typical structural anomalies and supported by a history of consanguinity. MGS, which was originally described by Meckel in 1822 and later by Gruber [1], is caused by the failure of mesodermal induction. Of the 200 cases which have been reported so far, the highest incidence has been observed in the Gujarati Indians, with 1 affected birth per 1,300 (carrier rate 1 in 18) [2]. MGS is a lethal, rare and autosomal recessive condition that commonly occurs in association with chromosome 17 [2]. This syndrome is characterised by cystic kidneys, occiptal encephalocele and post axial polydactly. Two out of the three major anomalies are sufficient for the definitive diagnosis. Many congenital anomalies are present, of which the most striking is occipital encephalocele [3]. This cconsists of extrusion of parts of the brain parenchyma that is fully covered by a dural sac. A 16–year–old primigravida presented in labour at 32 weeks of gestation with a preterm, premature rupture of membranes. A routine ultrasonography, which was done at 20 weeks, had diagnosed a foetus with several structural malformations that were suspected to be lethal. She continued the pregnancy on religious grounds. The ultrasonogram showed occipital encephalocele, polydactyly, oligohydramnios and cystic dysplasia of both kidneys. There was no history which was suggestive of an infectious origin for the malformations, but a genetic cause was suspected, as the patient had a consanguineous marriage. She delivered a 1.5 kg male foetus vaginally that had an occipital encephalocele [Table/Fig-1], a bell-shaped chest, a protuberant abdomen and post axial polydactyly of both hands and the left leg [Table/Fig-2]. On abdominal examination large masses were found, which were palpable in the lumbar regions. The baby died 2 hours after birth. A postmortem examination confirmed herniation of the brain and that both kidneys had multiple small cysts. A genetic analysis could not be done, as patient was unable to afford this investigation. The intra–natal and post–natal periods of the mother went on uneventfully. Based on the presence of classical features, a diagnosis of MGS was suggested. [Table/Fig-1]: Occipital encephalocele [Table/Fig-2]: Bell-shaped chest, protuberant abdomen and post axial polydactyly In MGS, the incidence of occipital encephalocele and post-axial polydactyly is 60% -80% and 55%-75%, respectively [2]. Renal disorders are noted in 95-100% of the cases. In this case, a foetal renal disorder like cystic dysplasia of bilateral kidneys was noted during autopsy; central nervous system defects and skeletal system malformations which included micrognathia were also present. In MGS most of the infants with are stillborns or they die hours or days after birth, the implicated cause being dysplastic kidneys that result in oligohydramnios, which ultimately leads to foetal pulmonary hypoplasia [2]. The longest known survivor lived only till 4 months [4]. The possible differential diagnoses are trisomy13, autosomal dominant polycystic kidney disease(PKD) and autosomal recessive Smith-Lemli-Opitz (SLO) syndrome [5]. In view of the high recurrence rates of MGS, subsequent pregnancies should be properly investigated by first trimester ultrasound scans, with an early recourse to a chorionic villus biopsy or amniocentesis, if it is needed. Though neonatal autopsy and genetic studies are gold standards for the diagnosis, detecting two out of the three major anomalies in the foetus, as has been mentioned above, is also sufficient for clinicians to arrive at a definitive diagnosis and for counselling the patients likewise in such hospital set-ups where neither is possible.

Meckel–Gruber syndrome (MKS) is a clinically and genetically heterogeneous ciliopathy characterized by a triad of occipital encephalocele, polycystic kidneys, and postaxial polydactyly. Pathogenesis of MKS is related to dysfunction of primary cilia. However, reports on MKS caused by Tectonic2 (TCTN2) mutations are scanty whilst. There is no direct evidence of ciliogenesis in such MKS patients. Here, we identified two novel nonsense variants of TCTN2 (c.343G > T, p.E115*; c.1540C > T, p.Q514*) in a Chinese MKS fetus. Compared to reported TCTN2-causing MKS patients, our case represented an endocardial pad defect, which was not reported previously. We also found primary cilia protruded normally from the surface of epithelial cells in the affected fetal kidney tubules compared to controls, indicating TCTN2 is not necessary for ciliogenesis in the kidney. To our knowledge, this is the first case of MKS fetus caused by TCTN2 mutations from China.

Meckel syndrome (MKS) is a pre‐ or perinatal multisystemic ciliopathic lethal disorder with an autosomal recessive mode of inheritance. Meckel syndrome is usually manifested with meningo‐occipital encephalocele, polycystic kidney dysplasia, postaxial polydactyly and hepatobiliary ductal plate malformation. Germline variants in CEP290 cause MKS4. In this study, we investigated a 35‐years‐old Chinese female who was 17+1 weeks pregnant. She had a history of adverse pregnancy of having foetus with multiple malformations. We performed ultrasonography and identified the foetus with occipital meningoencephalocele and enlarged cystic dysplastic kidneys. So, she decided to terminate her pregnancy and further genetic molecular analysis was performed. We identified the aborted foetus without postaxial polydactyly. Histological examination of foetal kidney showed cysts in kidney and thinning of the renal cortex with glomerular atrophy. Whole exome sequencing identified a novel homozygous variant (c.2144T>G; p.L715*) in exon 21 of the CEP290 in the foetus. Sanger sequencing confirmed that both the parents of the foetus were carrying this variant in a heterozygous state. This variant was not identified in two elder sisters of the foetus as well as in the 100 healthy individuals. Western blot analysis showed that this variant leads to the formation of truncated CEP290 protein with the molecular weight of 84 KD compared with the wild‐type CEP290 protein of 290 KD. Hence, it is a loss‐of‐function variant. We also found that the mutant cilium appears longer in length than the wild‐type cilium. Our present study reported the first variant of CEP290 associated with MKS4 in Chinese population.

A Gene for Meckel Syndrome Maps to Chromosome 11q13

Meckel - Gruber syndrome (MGS) is a lethal autosomal recessive disorder characterized by occipital meningoencephalocele, postaxial polydactyly, and cystic dysplastic kidneys. Here, we present a case in which recurrent MGS was diagnosed in the first trimester.

Diagnosis of the Meckel-Gruber syndrome at eleven to fourteen weeks' gestation