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Meckel syndrome (MKS) is a lethal, autosomal recessive, congenital syndrome caused by mutations in genes that encode proteins structurally or functionally related to the primary cilium. MKS is a malformative syndrome, most commonly characterized by occipital meningoencephalocele, polycystic kidney disease, liver fibrosis, and post- and (occasionally) preaxial polydactyly. To date, more than 10 genes are known to constitute the molecular background of MKS, displaying genetic heterogeneity. Individuals with MKS may resemble some phenotypic features of Joubert syndrome and related disorders, thus making diagnostic setting quite challenging. Here, we systematically reviewed the main clinical and genetic characteristics of MKS and its role among ciliopathies. more...

Background Although zebrafish embryos have been used to study ciliogenesis and model polycystic kidney disease (PKD), adult zebrafish remain unexplored. Methods Transcription activator-like effector nucleases (TALEN) technology was used to generate mutant for tmem67, the homolog of the mammalian causative gene for Meckel syndrome type 3 (MKS3). Classic 2D and optical-clearing 3D imaging of an isolated adult zebrafish kidney were used to examine cystic and ciliary phenotypes. A hypomorphic mtor strain or rapamycin was used to inhibit mTOR activity. Results Adult tmem67 zebrafish developed progressive mesonephric cysts that share conserved features of mammalian cystogenesis, including a switch of cyst origin with age and an increase in proliferation of cyst-lining epithelial cells. The mutants had shorter and fewer distal single cilia and greater numbers of multiciliated cells (MCCs). Absence of a single cilium preceded cystogenesis, and expansion of MCCs occurred after pronephric cyst formation and was inversely correlated with the severity of renal cysts in young adult zebrafish, suggesting a primary defect and an adaptive action, respectively. Finally, the mutants exhibited hyperactive mTOR signaling. mTOR inhibition ameliorated renal cysts in both the embryonic and adult zebrafish models; however, it only rescued ciliary abnormalities in the adult mutants. Conclusions Adult zebrafish tmem67 mutants offer a new vertebrate model for renal cystic diseases, in which cilia morphology can be analyzed at a single-nephron resolution and mTOR inhibition proves to be a candidate therapeutic strategy. more...

Cilia are plasma membrane protrusions that act as cellular antennae and propellers in eukaryotes. To achieve their sensory and motile functions, cilia maintain protein and lipid compositions that are distinct from those of the cell body. The transition zone (TZ) is a specialized region located at the ciliary base, which functions as a barrier separating the interior and exterior of cilia. The TZ comprises a number of transmembrane and soluble proteins. Meckel syndrome (MKS)1, B9 domain (B9D)1/MKS9, and B9D2/MKS10 are soluble TZ proteins that are encoded by causative genes of MKS and have a B9D in common. We here demonstrate the interaction mode of these B9D proteins to be MKS1–B9D2–B9D1 and demonstrate their interdependent localization to the TZ. Phenotypic analyses of MKS1-knockout (KO) and B9D2-KO cells show that the B9D proteins are involved in, although not essential for, normal cilia biogenesis. Rescue experiments of these KO cells show that formation of the B9D protein complex is crucial for creating a diffusion barrier for ciliary membrane proteins. more...

Primary cilia are signaling organelles that project from the apical surface of almost all vertebrate cells. The signaling capabilities of primary cilia stem from their unique membrane protein composition: even though the ciliary membrane is continuous with the plasma membrane, certain membrane proteins localize specifically to the ciliary membrane. This dissertation describes how the ciliary membrane protein composition is maintained, and how the complex responsible for ciliary membrane composition is localized. Using a combination of molecular biology, cell biology, and biochemistry, I have investigated the role of TMEM231 in the formation and function of the transition zone in cilia during development and in disease, and the role of INTU in localizing TMEM231 during ciliogenesis. I show that TMEM231 is a component of the Meckel Syndrome (MKS) complex, and is responsible for organizing the MKS complex at the transition zone. In the absence of Tmem231, mouse embryos display phenotypes similar to those found in MKS, which is a genetic disorder characterized by polydactyly, cystic kidneys, and exencephaly. Using co-immunoprecipitation, I confirmed that TMEM231 physically interacts with other known MKS complex components, including B9D1 and MKS1. In addition, I show that TMEM231 functions with the MKS complex, which is required for ciliary membrane proteins to localize properly. In collaboration with human geneticists, we identified compound heterozygous mutations in TMEM231 in Oro-facio-digital syndrome type III (OFD3) patients, as well as homozygous mutations in TMEM231 in MKS patients. I discovered that these mutations are hypomorphic, as they are unable to restore full ciliary membrane protein localization in a rescue assay. These findings confirm that TMEM231 is a functional component of the MKS complex, and suggest that the mutations identified in OFD3 and MKS patients underlie the disease phenotypes. In addition, I investigated the role of INTU in cilia function, because Intu mutant mice display phenotypes similar to MKS complex mutant mice. First, I confirm that INTU is necessary for cilia formation, and that this is not due to loss of IFT-B components. I observed that MKS complex components, including TMEM231 and TMEM67, are lost in the absence of Intu. Interestingly, another complex called the Nephronophthisis (NPHP) complex is also mislocalized. These results suggest that Intu is required for both NPHP and MKS complexes to localize properly. Finally, I looked at RPGRIP1L, the previously identified lynchpin of the NPHP and MKS complexes, and found that RPGRIP1L localizes normally in the absence of Intu. These data suggest that INTU functions downstream of RPGRIP1L to localize both the NPHP and MKS complexes. Cumulatively, I have shown that TMEM231 and INTU are required for cilia to form and function properly, and that cilia are important for regulating vertebrate development and adult tissue homeostasis. more...

Background Mutations in ciliary genes cause a spectrum of both overlapping and distinct clinical syndromes (ciliopathies). CEP120 and CC2D2A are paradigmatic examples for this genetic heterogeneity and pleiotropy as mutations in both cause Joubert syndrome but are also associated with skeletal ciliopathies and Meckel syndrome, respectively. The molecular basis for this phenotypical variability is not understood but basal exon skipping likely contributes to tolerance for deleterious mutations via tissue‐specific preservation of the amount of expressed functional protein. Methods We systematically reviewed and annotated genetic variants and clinical presentations reported in CEP120‐ and CC2D2A‐associated disease and we combined in silico and ex vivo approaches to study tissue‐specific transcripts and identify molecular targets for exon skipping. Results We confirmed more severe clinical presentations associated with truncating CC2D2A mutations. We identified and confirmed basal exon skipping in the kidney, with possible relevance for organ‐specific disease manifestations. Finally, we proposed a multimodal approach to classify exons amenable to exon skipping. By mapping reported variants, 14 truncating mutations in 7 CC2D2A exons were identified as potentially rescuable by targeted exon skipping, an approach that is already in clinical use for other inherited human diseases. Conclusion Genotype‐phenotype correlations for CC2D2A support the deleteriousness of null alleles and CC2D2A, but not CEP120, offers potential for therapeutic exon skipping approaches., Mutations in CEP120 and CC2D2A cause Joubert syndrome but are also associated with skeletal ciliopathies and Meckel syndrome, respectively. Here we annotate genetic variants described in CEP120‐ and CC2D2A‐associated disease and confirm more severe clinical presentations with biallelic truncating CC2D2A mutations. Combining in silico and ex vivo studies, we identify alternative basal exon skipping in the kidney, with possible relevance for organ‐specific disease manifestations and propose a multimodal approach to classify exons amenable to exon skipping. more...

Background: Antenatally detected occipital encephalocele and polycystic kidneys are a common presentation of ciliopathies like Joubert syndrome and Meckel Gruber syndrome which have considerable genetic and phenotypic overlap. Case reports: We describe 3 cases of antenatally diagnosed occipital encephalocele and enlarged kidneys with fetal autopsy, histopathology & exome sequencing results. A novel nonsense variant in the CEP290 gene was reported in first case (Meckel syndrome). The second case shows the importance of fetal exome where the parents were carriers for 2 ciliopathy genes (TMEM138 & SDCCAG8). Diagnosis in this case was confirmed by fetal exome sequencing (Joubert syndrome). Multiexon deletion in TMEM67 and KIF14 present in trans was identified in the third case (Meckel syndrome), likely resulting in digenic inheritance. Conclusion: We report 2 cases of Meckel syndrome with a novel variant and multiexon deletion, and 1 case of Joubert syndrome which depicts the limitations of preconceptional carrier screening in ciliopathies due to overlapping phenotypes. more...

To determine the diagnostic yield of exome sequencing (ES), a microarray analysis was carried out of fetuses with recurrent fetal structural anomalies (with similar anomalies in consecutive pregnancies). This is a systematic review conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The selected studies describing ES in fetuses with recurrent fetal malformation were assessed using the Standards for Reporting of Diagnostic Accuracy Studies (STARD) criteria for risk of bias. Incidence was used as the pooled effect size by single-proportion analysis using random-effects modeling (weighted by inverse of variance). We identified nine studies on ES diagnostic yield that included 140 fetuses with recurrent structural anomalies. A pathogenic or likely pathogenic variant was found in 57 fetuses, resulting in a 40% (95%CI: 26% to 54%) incremental performance pool of ES. As expected, the vast majority (86%: 36/42) of the newly identified diseases had a recessive inheritance pattern, and among these, 42% (15/36) of variants were found in homozygosity. Meckel syndrome was the monogenic disease most frequently found, although the genes involved were diverse. The ES diagnostic yield in pregnancies with recurrent fetal structural anomalies was 40% (57/140). Homozygous disease-causing variants were found in 36% (15/57) of the newly identified monogenic disorders. more...

Joubert syndrome (JS; MIM PS213300) is a rare, typically autosomal recessive disorder characterized by cerebellar vermis hypoplasia and a distinctive malformation of the cerebellum and brainstem identified as the “molar tooth sign” on brain MRI. Other universal features include hypotonia with later ataxia and intellectual disability/developmental delay, with additional features consisting of oculomotor apraxia and abnormal respiratory pattern. Notably, other, more variable features include renal cystic disease, typically nephronophthisis, retinal dystrophy, and congenital hepatic fibrosis; skeletal changes such as polydactyly and findings consistent with short-rib skeletal dysplasias are also seen in many subjects. These pleiotropic features are typical of a number of disorders of the primary cilium, and make the identification of causal genes challenging given the significant overlap between JS and other ciliopathy conditions such as nephronophthisis and Meckel, Bardet-Biedl, and COACH syndromes. This review will describe the features of JS, characterize the 35 known genes associated with the condition, and describe some of the genetic conundrums of JS, such as the heterogeneity of founder effects, lack of genotype-phenotype correlations, and role of genetic modifiers. Finally, aspects of JS and related ciliopathies that may pave the way for development of therapeutic interventions, including gene therapy, will be described. more...

Johann Friedrich Meckel (1781-1833) was a 19th century anatomist born into an eminent dynasty. He was a professor of anatomy, pathology, and zoology at the University of Halle, in Central Germany. The diverticulum, a congenital remnant of the vitellointestinal duct was named after him. Other eponyms include Meckel's cartilage, Meckel syndrome, and Meckel-Serres law of recapitulation. His concepts in comparative anatomy, embryology, and teratology anticipated Darwin. This review is a short tribute to this legend and his prolific contributions. LEVEL: Historic review, level V. more...

RESUMEN : El cilio primario es una estructura celular que durante muchos años se consideró como un vestigio sin relevancia. Con el paso de los años, se han descubierto diversas funciones celulares de las cuales este orgánulo microtubular es participe. Existen múltiples tipos de cilios en el organismo, siendo el cilio primario uno de los grandes desconocidos. Por ello, en esta revisión bibliográfica se resumen los tipos de cilios, para luego describir en detalle el cilio primario en la salud y la enfermedad. Con la aparición de nuevas enfermedades hereditarias, de mayor a menor gravedad, se han propuesto numerosas teorías que correlacionen las alteraciones de estructuras proteicas ciliares con el origen de dichas enfermedades. Así es que, a pesar del gran avance que se está llevando a cabo para intentar relacionar alteraciones genéticas causantes de enfermedades con un fenotipo claro, todavía quedan muchas cuestiones por resolver. En este Trabajo Fin de Grado se expone de una manera sencilla y breve, los progresos en relación al cilio primario y algunas de sus patologías asociadas como el Síndrome de riñón poliquístico o el Síndrome de Joubert. También se explicará brevemente la interacción entre el virus responsable de la COVID-19 y los cilios. ABSTRACT : The primary cilium is a cellular structure that for many years was considered irrelevant. Nevertheless, the functionality of this microtubular organelle has been revisited since it is involved in several cellular mechanisms. There are multiple types of cilia, being the primary cilia the great unknown. Therefore, this bibliographical assay describes the different types of this organelles to help the understanding of the primary cilium in the health and disease. New emerging genetic diseases have been described, which some of them have been proved to be lethal. This has made scientists carry out some theories that could bind together defects in ciliary protein structures and the origin of the diseases. Although there is a great progresstrying to understand the genetic and phenotypic characteristics of ciliopathies, it is still a conundrum. In this Final Project I am going to try to describe readily the developments within the primary cilia and its pathologies, like Polycystic kidney disease or Joubert Syndrome. The interaction between the virus responsible of COVID-19 and cilia will also be briefly explained. Grado en Medicina more...

Ciliopathies are inherited disorders caused by defects in motile and non-motile (primary) cilia. Ciliopathy syndromes and associated gene variants are often highly pleiotropic and represent exemplars for interrogating genotype-phenotype correlations. Towards understanding disease mechanisms in the context of ciliopathy mutations, we have used a leading model organism for cilia and ciliopathy research, Caenorhabditis elegans, together with gene editing, to characterise two missense variants (P74S and G155S) in mksr-2/B9D2 associated with Joubert syndrome (JBTS). B9D2 functions within the Meckel syndrome (MKS) module at the ciliary base transition zone (TZ) compartment and regulates the molecular composition and sensory/signalling functions of the cilium. Quantitative assays of cilium/TZ structure and function, together with knock-in reporters, confirm that both variant alleles are pathogenic in worms. G155S causes a more severe overall phenotype and disrupts endogenous MKSR-2 organisation at the TZ. Recapitulation of the patient biallelic genotype shows that compound heterozygous worms phenocopy worms homozygous for P74S. The P74S and G155S alleles also reveal evidence of a very close functional association between the B9D2-associated B9 complex and MKS-2/TMEM216. Together, these data establish C. elegans as a model for interpreting JBTS mutations and provide further insight into MKS module organisation. This article has an associated First Person interview with the first author of the paper., Editor’s choice: Genome editing was carried out in C. elegans to model and characterise two pathogenic missense variants of mksr-2/B9D2, P74S and G155S, from a compound heterozygous patient with Joubert syndrome. more...

The retinitis pigmentosa GTPase regulator interacting protein 1-like (RPGRIP1L) gene encodes a ciliary protein that is critical for processes related to brain development, including development of left-right asymmetry, sonic hedgehog signaling, and neural tube formation. RPGRIP1L is a risk factor for retinal degeneration, and rare, deleterious variants in the RPGRIP1L gene cause Joubert syndrome and Meckel syndrome, both autosomal recessive disorders. These syndromes are characterized by dysfunctional primary cilia that result in abnormal development – and even lethality in the case of Meckel syndrome. Genetic studies have also implicated RPGRIP1L in psychiatric disorders by suggestive findings from genome-wide association studies and findings from rare-variant exome analyses for bipolar disorder and de novo mutations in autism. In this study we identify a common variant in RPGRIP1L, rs7203525, that influences alternative splicing, increasing the inclusion of exon 20 of RPGRIP1L. We detected this alternative splicing association in human postmortem brain tissue samples and, using a minigene assay combined with in vitro mutagenesis, confirmed that the alternative splicing is attributable to the alleles of this variant. The predominate RPGRIP1L isoform expressed in adult brains does not contain exon 20; thus, a shift to include this exon may impact brain function. more...

Mutations in genes involved in the cilium-centrosome complex are called ciliopathies. Meckel-Gruber syndrome (MKS) is a ciliopathic lethal autosomal recessive syndrome characterized by genetically and clinically heterogeneous manifestations, including renal cystic dysplasia, occipital encephalocele and polydactyly. Several genes have previously been associated with MKS and MKS-like phenotypes, but there are still genes remaining to be discovered. We have used whole-exome sequencing (WES) to uncover the genetics of a suspected autosomal recessive Meckel syndrome phenotype in a family with 2 affected fetuses. RNA studies and histopathological analysis was performed for further delineation. WES lead to identification of a homozygous nonsense mutation c.256C>T (p.Arg86*) in CEP55 (centrosomal protein of 55 kDa) in the affected fetus. The variant has previously been identified in carriers in low frequencies, and segregated in the family. CEP55 is an important centrosomal protein required for the mid-body formation at cytokinesis. Our results expand the list of centrosomal proteins implicated in human ciliopathies and provide evidence for an essential role of CEP55 during embryogenesis and development of disease. more...

Key Clinical Message We report an otherwise healthy 32-year-old man with portal hypertension, variceal bleeding, and congenital hepatic fibrosis with ductal plate malformation. Genetic screening identified two TMEM67 mutations. Biallelic TMEM67 mutations are known to cause Joubert/Meckel syndrome or nephronopthisis with hepatic fibrosis, but have never been found in isolated hepatic fibrosis. more...

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. more...

Background Ciliopathies are an extensive group of autosomal recessive or X-linked disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. In large numbers of cases the genetic defect remains yet to be determined. The aim of this study is to describe the mutational frequency and phenotypic spectrum of the CEP120 gene. Methods Exome sequencing was performed in 145 patients with Joubert syndrome ( JS), including 15 children with oral-facial-digital syndrome type VI (OFDVI) and 21 Meckel syndrome (MKS) fetuses. Moreover, exome sequencing was performed in one fetus with tectocerebellar dysraphia with occipital encephalocele (TCDOE), molar tooth sign and additional skeletal abnormalities. As a parallel study, 346 probands with a phenotype consistent with JS or related ciliopathies underwent next-generation sequencing-based targeted sequencing of 120 previously described and candidate ciliopathy genes. Results We present six probands carrying nine distinct mutations (of which eight are novel) in the CEP120 gene, previously found mutated only in Jeune asphyxiating thoracic dystrophy ( JATD). The CEP120- associated phenotype ranges from mild classical JS in four patients to more severe conditions in two fetuses, with overlapping features of distinct ciliopathies that include TCDOE, MKS, JATD and OFD syndromes. No obvious correlation is evident between the type or location of identified mutations and the ciliopathy phenotype. Conclusion Our findings broaden the spectrum of phenotypes caused by CEP120 mutations that account for nearly 1% of patients with JS as well as for more complex ciliopathy phenotypes. The lack of clear genotype-phenotype correlation highlights the relevance of comprehensive genetic analyses in the diagnostics of ciliopathies. more...

The primary cilium is an organelle which plays an important role in the transduction of signals in the Wnt and Sonic hedgehog pathways. Abnormal or absent primary cilia result in various neurodevelopmental, retinal, renal, hepatic and musculoskeletal abnormalities. Joubert syndrome (JS) is a ciliopathy with a prevalence estimated to be between 1:80 000 and 1:100 000. JS occurs due to bi-allelic mutations in one of the 34 identified genes, all of which encode for protein components of the primary cilia. The presentation of JS is highly variable, however a clinical diagnosis can be established by the presence of the molar tooth sign on axial brain MRI, hypotonia in infancy, and developmental delay. JS is less severe than Meckel syndrome (MKS), which is another recessive, and often lethal, ciliopathy. This report outlines an interesting case of JS, in which two novel mutations in B9D1 were identified. This gene is not commonly associated with JS, and is often implicated in MKS. Functional mRNA study was helpful in delineating the pathogenic role of novel variants in this case. more...

A patient referred for prenatal diagnostics, after first-trimester ultrasound due to a previous child with Leber congenital amaurosis, was suggestive of a Meckel syndrome-like phenotype. Fetal autopsy confirmed the multiple anomalies, and whole-exome sequencing of the fetal DNA identified a pathogenic variant in the RPGRIP1 gene, previously identified in the elder sibling, and a variant causative of Meckel syndrome 1 in the MKS1 gene. Reporting the MKS1 mutation, which was present in heterozygous state in the elder sibling, as a secondary finding would have enabled the parents to be tested for carrier status of the same variant and appropriate counseling could have been provided prior to the onset of the pregnancy. Although the information may not be of great benefit in cases where the ultrasonographic changes can be recognized early, it would be of definitive help where diagnostic imaging in early pregnancy is not possible. more...

Background: The short-rib polydactyly (SRP) syndromes are rare skeletal dysplasias caused by abnormalities in primary cilia, sometimes associated with visceral malformations. Methods: The pathogenesis of ductal plate malformation (DPM) varies in different syndromes and has not been investigated in SRP. We have studied liver development in five SRP fetuses and pancreatic development in one SRP fetus, with genetically confirmed mutations in cilia related genes, with and without DPMs, using the immunoperoxidase technique, and compared these to other syndromes with DPM. Results: Acetylated tubulin expression was abnormal in DPM in SRP, Meckel syndrome, and autosomal recessive polycystic kidney disease (ARPKD), confirming ciliary anomalies. SDF-1 was abnormally expressed in SRP and two of three cases of autosomal dominant polycystic kidney disease (ADPKD) but not ARPKD or Meckel. Increased density of quiescent hepatic stellate cells was seen in SRP, Meckel, one of three cases of ARPKD, and two of three cases of ADPKD with aberrant hepatocyte expression of keratin 19 in SRP and ADPKD. Immunophenotypic abnormalities were present even in fetal liver without fully developed DPMs. The SRP case with DPM and pancreatic malformations showed abnormalities in the pancreatic head (influenced by mesenchyme from the septum transversum, similar to liver) but not pancreatic body (influenced by mesenchyme adjacent to the notochord). Conclusion: In SRP, there are differentiation defects of hepatocytes, cholangiocytes, and liver mesenchyme and, in rare cases, pancreatic mesenchymal anomalies. The morphological changes were subtle in early gestation but immunophenotypic abnormalities were present. Mesenchymal–epithelial interactions may contribute to the malformations. Birth Defects Research (Part A) 106:549–562, 2016. more...

The centrosomal protein 55 kDa (CEP55 (OMIM 610000)) plays a fundamental role in cell cycle regulation and cytokinesis. However, the precise role of CEP55 in human embryonic growth and development is yet to be fully defined. Here we identified a novel homozygous founder frameshift variant in CEP55, present at low frequency in the Amish community, in two siblings presenting with a lethal foetal disorder. The features of the condition are reminiscent of a Meckel-like syndrome comprising of Potter sequence, hydranencephaly, and cystic dysplastic kidneys. These findings, considered alongside two recent studies of single families reporting loss of function candidate variants in CEP55, confirm disruption of CEP55 function as a cause of this clinical spectrum and enable us to delineate the cardinal clinical features of this disorder, providing important new insights into early human development. more...

Meckel-Gruber syndrome is a severe ciliopathy first described in 1822. The worldwide incidence ranges from 1 : 1300 in Gujarati Indians to 1 : 140,000 in England. Twelve genetic mutations are associated with Meckel-Gruber syndrome (designated MKS1 through MKS12). In all cases, this disorder has shown autosomal recessive inheritance. The diagnosis of Meckel-Gruber syndrome is typically made by prenatal ultrasound examination in the first or second trimester. Meckel-Gruber syndrome is considered in an individual with a normal karyotype who has at least two of the three classic features: occipital encephalocele; large, polycystic kidneys; and postaxial polydactyly. Most affected individuals die in utero or mothers elect for termination of pregnancy. The postnatal mortality is 100% for individuals who survive to birth, with the longest survivor dying at 28 months. The major causes of death are pulmonary hypoplasia from oligohydramnios and liver disease. more...

The anatomical collection of the Anatomical Museum of Leiden University Medical Center (historically referred to as Museum Anatomicum Academiae Lugduno-Batavae) houses and maintains more than 13,000 unique anatomical, pathological and zoological specimens, and include the oldest teratological specimens of The Netherlands. Throughout four centuries hundreds of teratological specimens were acquired by more than a dozen collectors. Due to the rich history of this vast collection, teratological specimens can be investigated in a unique retrospective sight going back almost four centuries. The entire 19th century collection was described in full detail by Eduard Sandifort (1742-1814) and his son Gerard Sandifort (1779-1848). Efforts were made to re-describe, re-diagnose and re-categorize all present human teratological specimens, and to match them with historical descriptions. In the extant collection a total of 642 human teratological specimens were identified, including exceptional conditions such as faciocranioschisis and conjoined twins discordant for cyclopia, and sirenomelia. Both father and son Sandifort differed in their opinion regarding the causative explanation of congenital anomalies. Whereas, their contemporaries Wouter Van Doeveren (1730-1783) and Andreas Bonn (1738-1817) both presented an interesting view on how congenital anomalies were perceived and explained during the 18th and 19th centuries; the golden age of descriptive teratology. Although this enormous collection is almost 400 years old, it still impresses scientists, (bio)medical students, and laymen visiting and exploring the collections of the Museum Anatomicum in Leiden, The Netherlands. more...

Phenotypic analysis has been practised in many different ways, the most common being the recognition of normal and abnormal physical and biochemical characteristics and their patterns of inheritance. As different tools became available to analyze the characteristics of individuals the study of the phenotype and consequently of the genotype became more sophisticated. By the mid 1970’s ultrasonography became a major tool in the analysis of human disease, and more recently it has contributed to the analysis of the human fetal phenotype in utero. This method, when used in conjunction with cytogenetic and biochemical analysis of the amniotic fluid, constitutes the main thrust of genetic prenatal diagnosis today. This paper describes and proposes the systematic use of ultrasonography, in conjunction with biochemical and cytogenetic tests to examine pregnancies at risk of congenital and inherited diseases and those that show signs of abnormality. We have examined 1500 fetuses and have detected conditions that affect only one system, like the skeletal dysplasias (osteogenesis imperfecta, thanatophoric dysplasia, diastrophic dwarfism, achondrogenesis I, Jeune syndrome and many others), neural tube defects, gastroschisis, multiple congenital malformations syndromes (Vater, Vacterl, Weyers olygodactyly, Meckel syndrome, and others). The analysis of the functionality of the fetus is one of the major achievements of genetic prenatal diagnosis by ultrasonography. more...

To investigate the sonographic and clinical genotype–phenotype correlations in autosomal recessive polycystic kidney disease (ARPKD) and other cystic kidney diseases (CKD) in a large cohort of prenatally detected fetuses with hereditary CKD. We retrospectively studied the clinical and diagnostic data of 398 patients referred with prenatal ultrasound findings suggestive of CKD between 1994 and 2010. Cases with confirmed hereditary CKD (n = 130) were analyzed as to their prenatal ultrasound findings, genotype, and possible predictors of clinical outcome. ARPKD was most common in our non-representative sample. Truncating PKHD1 mutations led to a significantly reduced neonatal prognosis, with two such mutations being invariably lethal. Sonographically visible kidney cysts occurred in only 3% of ARPKD cases. Renal abnormalities in Meckel syndrome (MKS) appeared earlier than in ADPKD (19.6 ± 3.7 vs. 29.8 ± 5.1 GW) or ARPKD (19.6 ± 3.7 vs. 30.2 ± 1.2 GW). Additional CNS malformations were not found in ARPKD, but were highly sensitive for MKS. Pulmonary hypoplasia, oligo/anhydramnios (OAH), and kidney enlargement were associated with a significantly worse neonatal prognosis. Genotype, sonographic signs of OAH, enlarged kidney size, and pulmonary hypoplasia can be useful predictors of neonatal survival. We propose sonographic morphological criteria for ARPKD, ADPKD, MKS, and renal cyst and diabetes syndrome (RCAD). We further propose a clinical diagnostic algorithm for differentiating cystic kidney diseases. more...

Oral-facial-digital syndromes (OFDS) represent a heterogeneous group of rare developmental disorders affecting the mouth, the face and the digits. Additional signs may involve brain, kidneys and other organs thus better defining the different clinical subtypes. With the exception of OFD types I and VIII, which are X-linked, the majority of OFDS is transmitted as an autosomal recessive syndrome. A number of genes have already found to be mutated in OFDS and most of the encoded proteins are predicted or proven to be involved in primary cilia/basal body function. Preliminary data indicate a physical interaction among some of those proteins and future studies will clarify whether all OFDS proteins are part of a network functionally connected to cilia. Mutations in some of the genes can also lead to other types of ciliopathies with partially overlapping phenotypes, such as Joubert syndrome (JS) and Meckel syndrome (MKS), supporting the concept that cilia-related diseases might be a continuous spectrum of the same phenotype with different degrees of severity. To date, seven of the described OFDS still await a molecular definition and two unclassified forms need further clinical and molecular validation. Next-generation sequencing (NGS) approaches are expected to shed light on how many OFDS geneticists should consider while evaluating oral-facial-digital cases. Functional studies will establish whether the non-ciliary functions of the transcripts mutated in OFDS might contribute to any of the phenotypic abnormalities observed in OFDS. Electronic supplementary material The online version of this article (doi:10.1186/s13630-016-0034-4) contains supplementary material, which is available to authorized users. more...