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Meckel Syndrome Panel

January 16, 2018

Disease synonyms

Meckel-Gruber syndrome, Meckel syndrome, MKS, MES, Dysencephalia splanchnocystica, Gruber syndrome

Inheritance pattern

Autosomal recessive 

Clinical features

Meckel syndrome (MES), also known as Meckel-Gruber syndrome, belongs to the group of ciliopathies caused by dysfunction of primary cilia during embryogenesis. Cilia are highly evolutionarily conserved organelles which project from the surface of every cell type in the body, playing an important role both during embryo development and in adult life. In accordance with the wide range of functions cilia perform, a number of inherited diseases, known as ciliopathies, have been increasingly linked to defects in genes which affect cilia assembly or function 1, 2. Ciliopathies share many clinical features, with renal, retinal, and hepatic involvement frequently observed with skeletal malformations and central nervous system developmental defects. The most severe are lethal in the early gestation or neonatal periods 3. Many genes are associated with ciliopathies with different clinical manifestations (see Table 1). 

Meckel-Gruber syndrome is characterized by a triad of symptoms: occipital encephalocele, large polycystic kidneys, and postaxial polydactyly. The incidence of Meckel-Gruber syndrome is 1 per 13,250-140,000 live births worldwide, while individuals of Finnish descent have a higher incidence of this disease, 1 per 9,000 live births 4. The highest incidence is reported in the Gujarati Indians, with 1 affected birth per 1,300 (carrier rate 1 in 18) 5, 6.

The major clinical features observed in patients affected with MKS include the following 4:

  • Cystic kidneys (observed in 97.7% of affected patients)
  • Polydactyly (87.3%)
  • Encephalocele (83.8%)
  • Fibrotic/cystic changes of the liver (65.5%, as identified via postmortem examination)
  • Other CNS anomalies (51.4%)
  • Orofacial clefts (31.8%)

 In addition to Meckel Gruber syndrome, additional disorders also belong to this group of primary ciliopathies (see Table 1): 

Table 1: Clinical and genetic features of major ciliopathies.

Disease Gene/Genes Clinical features
Bardet-Biedl syndrome (BBS) ARL6, BBIP1, BBS1-12, CCDC28B, CEP290, IFT27, LZTFL1, MKKS, MKS1, SDCCAG8, TMEM67, TRIM32, WDPCP

Polydactyly, cystic kidneys, retinitis pigmentosa, obesity, situs inversus.

McKusick–Kaufman syndrome (MKS) MKKS

Hydrometrocolpos, post-axial polydactyly, congenital heart disease.

Alström syndrome (AS) ALMS1

Cone-rod dystrophy, hearing loss, obesity, cardiomyopathy, hepatic and renal dysfunction

Nephronophthisis (NPH) NPHP1-4, INVS, ANKS6, IQCB1, CEP164, CEP290, GLIS2, RPGRIP1L, NEK8, SDCCAG8, ZNF423

Renal fibrosis, polyuria, polydipsia, fatigue, anemia, renal failure

Meckel-Gruber syndrome (MGS) MKS1, TMEM216, TMEM67, CEP290, RPGRIP1L, CC2D2A, NPHP3, TCTN2, B9D1, B9D2, TMEM231

Renal cystic dysplasia, hepatic fibrosis, occipital encephalocoele, microcephaly, polydactily, cleft lip/palate

Joubert syndrome (JS) AHI1, ARL13B, CC2D2A, CEP290, CSPP1, EXOC8, GLI3, INPP5E, MKS1, NEK8, NPHP1/3, OFD1 and others

Hypotonia, ataxia, psychomotor delay, oculomotor apraxia, macrocephaly, facial abnormalities 

Senior–Løken syndrome (SLS) CEP290, NPHP1-4, QCB1, SDCCAG8

Retinitis pigmentosa and renal disease

Orofaciodigital syndrome (OFD) OFD1

Malformations of oral cavity, face, digits, cystic kidneys, polydactyly

Ellis-van Creveld syndrome (EVC) EVC1, EVC2

Short ribs, polydactyly, growth retardation, ectodermal, cardiac defects

Jeune syndrome IFT80

Short ribs, biliary dysgenesis, renal cystogenesis, polydactyly, retinal degeneration.

Cranioectodermal dysplasia, CED IFT122, WDR35

Cranioectodermal dysplasia, renal cysts and dolichocephaly 

Leber’s congenital amaurosis (LCA) AIPL1, CEP290, CRB1, CRX, GUCY2D, IMPDH1, IQCB1, LCA5, LRAT, NMNAT1, RDH12, RPE65, RPGRIP1 and others

Severe retinal dystrophy, nystagmus, photophobia, hyperopia and keratoconus 

McKusick-Kaufman syndrome (MKS) is characterized by the combination of postaxial polydactyly, congenital heart disease, and hydrometrocolpos in females and genital malformations in males (most commonly hypospadias, cryptorchidism, and chordee). Pathogenic variants in MKKS were detected in the Amish with MKS, the only family definitely known to have this phenotype. The variant detection frequency for MKKS variants in individuals with MKS is unknown. However, pathogenic variants in MKKS/BBS6 are found in approximately 4.8% of individuals with BBS 7. Individuals with MKS in the Amish population are all homozygous for the pathogenic variants p.His84Tyr or p.Ala242Ser 8. Although the frequency of p.Ala242Ser is nearly 1% in the general population, the combination of p.His84Tyr and p.Ala242Ser is rare and the frequency is unknown.

Joubert syndrome (JS) is characterized by three primary findings: a distinctive cerebellar and brain stem malformation called the molar tooth sign, hypotonia, and developmental delays. Approximately a quarter of patients develop juvenile nephronophtisis and retinal dystrophy, termed cerebello-oculo-renal syndrome. Several additional clinical features have been reported, including occipital encephalocele, polymicrogyria, cystic kidneys, polydactyly, hepatic fibrosis, and ocular coloboma thus overlapping with the lethal, recessive disorder Meckel Gruber syndrome. JS is associated with bi-allelic pathogenic variants in more than 30 different genes, including CEP290, AHI1, MKS1 and others (see Table 1).

Bardet-Biedl syndrome (BBS) is characterized by rod-cone dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotropic hypogonadism, complex female genitourinary malformations, and renal abnormalities. Nearly all patients with BBS are obese (98%) 2, 15. More than 20 genes have been associated with BBS, including BBS1, BBS10, BBS2, MKKS, MKS1, TTC8, and others (see Table 1). 

Nephronophthisis (NPH) is another autosomal recessive kidney disease characterized by renal tubular atrophy and progressive interstitial fibrosis with later development of medullary cysts. NPH is caused by pathogenic variants in at least 19 genes (see Table 1). A homozygous, approximately 290-kb deletion of NPHP1 is identified in approximately 25% of individuals with juvenile nephronophthisis 11.

Oral-facial-digital syndrome describes a heterogeneous group of disorders characterized by facial features, oral abnormalities, and digital anomalies such as polydactyly. Based on other associated clinical features, at least 13 clinical subtypes have been described. These features also overlap considerably with Meckel syndrome, short rib polydactyly syndrome, and JS. Of the genes identified for OFD thus far, all have ciliary roles, and several overlap with JS. Oral-facial-digital syndrome type I (OFD1) is usually lethal for males during gestation and predominantly affects females. More than 80% of OFD1-affected patients can be diagnosed using gene sequencing of the OFD1 gene 12, while about 6% of OFD1-affected carry an OFD1 gene deletion 12.

Leber congenital amaurosis (LCA), a severe dystrophy of the retina, typically becomes evident in the first year of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia, and keratoconus. Visual acuity is rarely better than 20/400. A characteristic finding is Franceschetti's oculodigital sign, comprising eye poking, pressing, and rubbing. The appearance of the fundus is extremely variable. While the retina may initially appear normal, a pigmentary retinopathy reminiscent of retinitis pigmentosa is frequently observed later in childhood. The electroretinogram is characteristically "nondetectable" or severely subnormal. Pathogenic variants in at least 17 genes cause LCA, and pathogenic variants in CEP290 account for about 20% of LCA, with one homozygous intronic pathogenic variant accounting for at least 20% of isolated congenital blindness in European 20

Alström syndrome (AS) is characterized by cone-rod dystrophy, obesity, progressive sensorineural hearing impairment, dilated or restrictive cardiomyopathy, insulin resistance syndrome, and multiple organ failure. Cone-rod dystrophy presents as progressive visual impairment, photophobia, and nystagmus usually starting between birth and age 15 months. ALMS1 is the only known gene associated with Alström syndrome 13 (see Table 1).

Senior–Løken syndrome (SLS) is another ciliopathy characterized by major clinical features of nephronophthisis and retinal dystrophy. The major symptoms of this disease include polyuria, polydipsia, secondary eneuresis and anemia, which progress to endstage renal disease. Ocular features include congenital or early-onset severe visual loss, due to retinal dystrophy. NPHP1, INVS, NPHP3, NPHP4, IQCB1, CEP290, and SDCCAG8 genes have been associated with SLS (see Table 1).

Ellis-van Creveld syndrome (EVC) is a rare inherited ciliopathy characterized by chondrodysplasia with acromelic growth retardation, polydactyly, ectodermal dysplasia with dystrophy of the nails, and congenital heart disease. The two genes known to be associated with EVC are EVC1 and EVC2 (see Table 1).

Cranioectodermal dysplasia (CED) belongs to the group of ciliopathies characterized primarily by skeletal involvement, ectodermal and facial features. Major clinical findings include narrow thorax, shortened proximal limbs, brachydactyly, widely-spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails, joint laxity, growth retardation, and characteristic facial features. About 40% of CED-affected patients have a biallelic pathogenic variants in one of the following genes: IFT122, WDR35 (IFT121), WDR19 (IFT144), or IFT43 (previously known as C14orf179) 14.

Jeune syndrome is an autosomal recessive chondrodysplasia characterized by respiratory insufficiency due to the narrow and slender ribs and abnormal cage formation 15. Affected newborns and infants showed multisystem involvement, such as biliary dysgenesis with portal fibrosis and bile duct proliferation, renal cystogenesis and failure, polydactyly, and retinal degeneration. Pathogenic variants in the IFT80 gene have been reported as disease-causing 15.

Meckel syndrome can be caused by pathogenic variants in one of the following genes: MKS1, TMEM216, TMEM67, CEP290, RPGRIP1L, CC2D2A, NPHP3, TCTN2, B9D1, B9D2, and TMEM231. These genes encode proteins which play roles in the structure and function of cillia. Pathogenic variants in these genes affect a variety of tissues and organ systems in which the functions of the cilium-centrosome complex are critical. An overview of Meckel syndrome associated genes is given in Table 2: 

Abbreviations: Joubert syndrome (JS); Bardet-Biedl syndrome (BBS); Nephronophthisis (NPH); Alström syndrome (AS); McKusick-Kaufman syndrome (MKS); Oral-facial-digital syndrome (OFD); Senior–Løken syndrome (SLS); Leber congenital amaurosis (LCA),  Ellis-van Creveld syndrome (EVC); Cranioectodermal dysplasia (CED); Renal-hepatic-pancreatic dysplasia (RHPD).

The treatment and management of Meckel-Gruber syndrome includes only symptomatic approaches, such as cardiac or neurosurgical interventions, restoration of respiratory pathways. Infants and children with abnormal breathing may require stimulatory medications, supplemental oxygen, mechanical support, or tracheostomy. Other interventions may include occupational and physical therapy, speech therapy, and special educational support, including special programs for the visually impaired. Surgery may be required for polydactyly and symptomatic ptosis and/or strabismus. Nephronophthisis, end-stage renal disease, liver failure and/or fibrosis are treated with standard approaches.

CENTOGENE offers sequencing and deletion/duplication analysis of genes in the Meckel syndrome panel (MKS1, TMEM216, TMEM67, CEP290, RPGRIP1L, CC2D2A, NPHP3, TCTN2, B9D1, B9D2, TMEM231). 

Differential diagnosis

The differential diagnosis of Meckel syndrome includes the following diseases - depending on the major presenting symptoms:

  • Bardet-Biedl syndrome
  • Joubert syndrome
  • Larsen syndrome
  • Trisomy 13
  • Hydrocephalus
  • Smith-Lemli-Opitz Syndrome
  • Carbohydrate-deficient glycoprotein syndrome
  • Hydrolethalus syndrome.

Diagnostic strategy

CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free Whole Genome Sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage. 

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for Meckel syndrome using NGS Panel Genomic targeted towards this specific phenotype:

Step 1:       Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Meckel syndrome panel.

Step 2:       If no pathogenic variant is identified after analysis of the Meckel syndrome panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.   

Referral reasons

The following individuals are candidates for Meckel syndrome gene testing:

  • Individuals with a family history of Meckel syndrome and presentation of the most common symptoms, including visual and hearing abnormalities
  • Individuals without a positive family history, but with symptoms resembling Meckel syndrome
  • Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Sequencing, deletion/duplication of Meckel syndrome related genes should be performed in all individuals suspected of having Meckel syndrome . In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of variants, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of Meckel syndrome, identify at-risk family members, provide information on reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.