Meckel Syndrome, Type 2

A number sign (#) is used with this entry because of evidence that Meckel syndrome type 2 (MKS2) is caused by homozygous mutation in the TMEM216 gene (613277) on chromosome 11q12.

Mutation in the TMEM216 gene also causes Joubert syndrome type 2 (JBTS2; 608091).

Description

Meckel syndrome is a rare autosomal recessive lethal condition characterized by an occipital meningoencephalocele, enlarged kidneys with multicystic dysplasia and fibrotic changes in the portal area of the liver and with ductal proliferation, and postaxial polydactyly. For a more complete phenotypic description and information on genetic heterogeneity, see MKS1 (249000).

Clinical Features

Valente et al. (2010) reported 3 fetuses from 2 Tunisian families with Meckel syndrome-2. Common clinical features included cystic kidneys, polydactyly, bile duct proliferation, and bowing of the long bones. Two had meningocele, 1 had anencephaly, and 2 had cleft palate. One of the fetuses also had microphthalmia, intrauterine growth retardation, and hypoplastic external genitalia. Six affected fetuses of 3 Palestinian families were also affected. The most common clinical features included encephalocele, cystic kidneys, bile duct proliferation, and polydactyly.

Mapping

The gene responsible for MKS in Finland (MKS1; 609883) was mapped to chromosome 17q21-q24 by Paavola et al. (1995) who demonstrated that several non-Finnish families did not show linkage to 17q. Studying a subset of Middle Eastern and northern African MKS families, Roume et al. (1998) likewise excluded the disease gene from close proximity to the Finnish MKS gene (Roume et al., 1997).

By homozygosity mapping in 7 families that did not show linkage to 17q, Roume et al. (1998) mapped a second MKS locus (MKS2) to 11q13 (maximum lod score of 4.41 at a recombination fraction of 0.01). The affected fetuses of southern Tunisian ancestry shared a particular haplotype at D11S911 and D11S906, suggesting that a founder effect was involved. A subset of the affected fetuses harbored a severe cerebral phenotype first described by Ahdab-Barmada and Claasen (1990). The observation supported the clinical and genetic heterogeneity of MKS. Roume et al. (1998) pointed out that the D11S911-D11S906 interval encompassing the disease gene also encompasses PHOX2A (ARIX; 602753) (Merscher et al., 1997), a gene strongly expressed in the mouse hindbrain (Pattyn et al., 1997).

In a reanalysis of families with Meckel syndrome mapping to chromosome 11q13, Valente et al. (2010) assigned the MKS2 locus to a region between rs1113480 and rs953894, indicating possible allelism with JBTS2.

Molecular Genetics

In 3 fetuses from 2 Tunisian families with Meckel syndrome-2, Valente et al. (2010) identified a homozygous 341T-G mutation in the TMEM216 gene (L114R; 613277.0003). Haplotype analysis indicated a common founder for the 2 families. Six affected fetuses of 3 Palestinian families with Meckel syndrome-2 had a different truncating mutation in the TMEM216 gene (613277.0004). Haplotype analysis showed that 2 of the Palestinian families were related. Overall, 3 different TMEM216 mutations were found in 6 families with MKS2, and 4 different TMEM216 mutations were found in 14 families with Joubert syndrome-2 (JBTS2; 608091), indicating that these disorders are allelic. A Turkish family had 2 affected patients: 1 with Joubert syndrome and a fetus with Meckel syndrome, indicating that the 2 clinical disorders are part of the same spectrum.