(+) = feature is uncommon but has been described; + = feature is present in some cases; ++ = Major feature; HLS = hydrolethalus syndrome; NPHP = nephronophthisis; LCA = Leber congenital amaurosis; BBS = Bardet-Biedl syndrome; MORM = mental retardation, truncal obesity, retinal dystrophy, micropenis [Jacoby et al 2009]; OFD = oral-facial-digital syndrome; PD = polydactyly; JATD = jeune asphyxiating thoracic dystrophy; SNHL = sensorineural hearing loss

May include COACH syndrome: cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis

This refers to retinal disease plus kidney disease; terms used in the past include: Senior-Løken syndrome (retinopathy and juvenile-onset nephronophthisis); Dekaban-Arima syndrome (retinopathy, cystic dysplastic kidneys).

See Genetically Related Disorders for details.

The most common clinical association in those with biallelic AHI1 pathogenic variants is retinal dystrophy, present in approximately 80% [Valente et al 2008]. Early-onset congenital blindness [Valente et al 2006a] and liver involvement [Vilboux et al 2017] have been described.

Renal disease consistent with nephronophthisis has also been described [Parisi et al 2006, Utsch et al 2006].

Dixon-Salazar et al [2004], Gleeson et al [2004]

The phenotype most closely resembles pure or classic Joubert syndrome, with several individuals exhibiting preaxial, postaxial, and/or mesaxial polydactyly and a few with retinal involvement [Srour et al 2015] or liver involvement [Vilboux et al 2017]. None of the affected individuals (ranging in age from 1.5 to 52 years) has evidence of renal impairment or liver disease [Srour et al 2012a, Srour et al 2012b, Srour et al 2015]. Pathogenic variants in this gene also cause OFD VI, with features of preaxial and/or mesaxial polydactyly and hypothalamic hamartoma typical [Lopez et al 2014, Romani et al 2015].

Pathogenic variants in this gene are the cause of JS in the original family described by Joubert et al [1969]. Several pathogenic variants recur in the French Canadian population found in the lower St. Lawrence region of Quebec province [Srour et al 2012b, Srour et al 2015].

Kroes et al [2016]

Hepatic involvement has been described [Gorden et al 2008, Noor et al 2008].

Those with pathogenic variants in CC2D2A have an increased likelihood of ventriculomegaly and seizures [Bachmann-Gagescu et al 2012].

Srour et al [2012a]

Null alleles are associated with the Meckel syndrome phenotype and missense and/or hypomorphic variants with JS [Tallila et al 2008, Mougou-Zerelli et al 2009].

Up to 50% of individuals with both retinal and renal involvement harbor biallelic pathogenic variants in CEP290 [Valente et al 2008].

The phenotypic spectrum is very broad, including congenital blindness, ocular colobomas, renal disease, encephaloceles, septal heart disease, and situs abnormalities.

Shaheen et al [2014], Vilboux et al [2017]

Pathogenic variants in this gene have been described in phenotypes ranging from classic JS with occasional retinopathy and sensorineural hearing loss [Akizu et al 2014] to the JS-JATD phenotype with features of Jeune skeletal dysplasia [Tuz et al 2014] to a lethal MKS-like phenotype [Shaheen et al 2014]. Thin corpus callosum, occipital encephalocele, and heterotopias have also been described [Akizu et al 2014, Tuz et al 2014].

Jacoby et al [2009]

Pathogenic variants in this gene cause a wide spectrum of ciliopathy phenotypes, from "pure" JS with relatively mild manifestations and impairment [Bachmann-Gagescu et al 2015b, Roosing et al 2015] to features of Jeune asphyxiating thoracic dystrophy (small chest, short ribs, short stature) [Alby et al 2015, Malicdan et al 2015] to severe features of hydrolethalus syndrome with hydrocephalus and fetal or perimatal demise [Alby et al 2015]. This broad range of phenotypes is not explained by the nature of the pathogenic variants, as many afftected individuals have homozygous or compound heterozygous truncating variants due to frameshifts, aberrant splice, or nonsense variants.

Individuals with JS caused by MKS1 pathogenic variants have at least one variant with partial function (e.g., a missense variant that retains some function), in contrast to more severe variants described in those with MKS [Romani et al 2014, Slaats et al 2016]. Most of the affected individuals have a relatively mild phenotype, characterized by classic JS with or without retinal dystrophy. Only one reported individual (out of a group of 9 with pathogenic variants in this gene) had additional features of renal echogenicity, liver fibrosis, and postaxial polydactyly [Slaats et al 2016].

Some individuals with biallelic pathogenic variants in NPHP1 and JS have a distinctive appearance of the molar tooth sign: elongated but thin superior cerebellar peduncles and milder vermis hypoplasia [Parisi et al 2004a].

RPGRIP1L pathogenic variants also cause Meckel syndrome. Of note, more severe loss-of-function pathogenic variants predict a more severe (and in many cases, lethal) Meckel phenotype [Delous et al 2007, Wolf et al 2007].

A limited number of individuals with pathogenic variants in this gene has been described; thus, the phenotypic spectrum is unknown [Sang et al 2011].

Shaheen et al [2011]

Biallelic pathogenic variants in TMEM67 were present in 53% of those with ocular coloboma regardless of liver status [Doherty et al 2010].

Biallelic pathogenic variants in TMEM67 account for 70% of all JS with liver involvement [Doherty et al 2010, Iannicelli et al 2010].

Baala et al [2007], Brancati et al [2009], Doherty et al [2010], Vilboux et al [2017]

More severe loss-of-function variants in TMEM67 have been identified in individuals with lethal forms of Meckel syndrome [Smith et al 2006], in comparison with variants with partial function causing JS with hepatic disease or nephronophthisis and liver fibrosis in the absence of the molar tooth sign and other neurologic symptoms [Otto et al 2009, Doherty et al 2010].

Nephronophthisis and polydactyly are common; some individuals have features of OFD [Edvardson et al 2010, Valente et al 2010].