Prepair 1000+

Gene: TMEM67

Green List (high evidence)

Multiple AR phenotypes ciliopathy spectrum:
- COACH - cerebellar vermis hypo/aplasia, oligophrenia, ataxia, ocular coloboma, and hepatic fibrosis (overlap with Joubert but significant liver involvement. Onset in infancy, considered to be part of the spectrum of Joubert syndrome and Meckel syndrome (OMIM).
- Joubert -psychomotor delay, hypotonia, ataxia, oculomotor apraxia, and neonatal breathing abnormalities. Cerebellar abnormalities (molar tooth sign)
- Meckel (MKS) - pre- or perinatal lethal malformation syndrome characterized by renal cystic dysplasia and variably associated features including developmental anomalies of the central nervous system (typically occipital encephalocele), hepatic ductal dysplasia and cysts, and postaxial polydactyly. Lethal in utero or in the perinatal period (OMIM).
- Nephronophthisis (NPH) - renal interstitial infiltration with fibrosis, tubular atrophy with basement membrane disruption, and cyst development at the corticomedullary border. Hepatic fibrosis is also present. The clinical presentation includes polyuria, polydipsia, anemia, and growth retardation. End-stage renal disease develops in the first or second decade of life. Onset in childhood (OMIM).
- OMIM also lists ?RHYNS syndrome (Retinitis pigmentosa, HYpopituitarism, Nephronophthisis and Skeletal dysplasia), but only one patient has been reported (PMID: 29891882).

There is striking clinical and genetic overlap among some ciliopathies, namely Joubert syndrome and related disorders (JSRD), Meckel syndrome and Nephronophthisis. Therefore, genotype-phenotype correlations are only partly understood (PMID: 20232449).

A preliminary correlation has been observed between truncating mutations and the occurrence of MKS, while missense mutations are more frequently detected in association to less severe phenotypes such as COACH and NPH. In addition, a differential distribution of mutations along the gene in lethal (MKS) versus non-lethal (JSRD and NPH) phenotypes can be observed. MKS patients have a significant enrichment of missense mutations in exons 8 to 15, especially when in combination with a truncating mutation (PMID: 20232449).

Created: 20 Jan 2025, 11:59 p.m. | Last Modified: 20 Jan 2025, 11:59 p.m.

Panel Version: 1.1257

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
COACH syndrome 1 MIM#216360; Joubert syndrome 6 MIM#610688; Meckel syndrome 3 MIM#607361; Nephronophthisis 11 MIM#613550

Publications

• 29891882
• 20232449
• 26092869
• 27336129