Ciliopathy Panel

Ciliopathies are a group of genetic disorders caused by disruption of formation or function of cilia. Ciliary dysfunction results in a broad range of phenotypes, including renal cystic and hepatobiliary disease, situs abnormalities, retinal degeneration, cerebellar anomalies, postaxial polydactyly, bronchiectasis and infertility. See individual disease summaries for information about clinical features and spectra of pathogenic variants.

Joubert (JBTS) Syndrome

Joubert Syndrome and related disorders (JSRD) are marked by hypotonia, abnormal ocular movements, neonatal respiratory difficulties, intellectual disability, hypoplasia of the cerebellar vermis, and malformation of the brainstem. The brain malformations lead to the "molar tooth sign" on cranial MRI, which is pathognomonic for JSRD. Other variable JSRD features include cystic kidneys, nephronophthisis, retinal dystrophy, ocular coloboma, occipital encephalocele, polydactyly, ataxia, and hepatic fibrosis. For more information, see Parisi and Glass. 2017. PubMed ID: 20301500; Doherty 2009. PubMed ID: 19778711; Parisi et al. 2007. PubMed ID: 17377524; Brancati et al. 2010. PubMed ID: 20615230.

Meckel Gruber Syndrome (MKS)

Meckel-Gruber Syndrome (MKS) is a lethal autosomal recessive condition, also marked by brain malformation, cystic renal disease and polydactyly (Alexiev et al. 2006. PubMed ID: 16879033; Hartill et al. 2017. PubMed ID: 29209597). In MKS, the pathognomonic feature is occipital encephalocele, which is generally identified during routine sonography between 12 and 20 weeks of gestation. MKS is a common cause of prenatal echogenic kidneys (Chaumoitre et al. 2006. PubMed ID: 17094077). Nearly all MKS infants are stillborn or die shortly after birth (Hartill et al. 2017. PubMed ID: 29209597; Parisi and Glass. 2017. PubMed ID: 20301500).

Bardet-Biedl Syndrome

Bardet-Biedl Syndrome (BBS) is an autosomal recessive disorder marked by primary features of obesity, polydactyly, pigmentary retinopathy, hypogonadism, renal anomalies and mental retardation (Elbedour et al. 1994. PubMed ID: 7802002; Sheffield 2010. PubMed ID: 20697559). Secondary features include diabetes, hypertension and congenital heart defects (Green et al. 1989. PubMed ID: 2779627). Although BBS is a rare condition, diagnosis is complicated by the fact that many of the clinical features (i.e. obesity, diabetes, hypertension and developmental delay) are common. In addition, many of the BBS clinical features overlap with those of other well-described developmental disorders, including Meckel-Gruber Syndrome (MKS), Joubert Syndrome (JBTS), Nephronophthisis (NPH), Senior-Loken Syndrome (SLS) and Leber Congenital Amaurosis (LCA). Thus, molecular testing is often useful for confirmation of a clinical diagnosis and to aid in the treatment and management of BBS.

Nephronophthisis and Senior-Loken syndrome

Nephronophthisis (NPH) is the most common genetic cause of progressive renal failure in children and young adults. NPH is characterized by polyuria, growth retardation and progressive deterioration of renal function with normal or slightly reduced kidney size (Hildebrandt et al. 1997. PubMed ID: 9326933; Hildebrandt et al. 2009. PubMed ID: 19118152). Nephronophthisis, when associated with Leber Congenital Amaurosis, is known as Senior-Loken syndrome (SLS) (Otto et al. 2005. PubMed ID: 15723066; Hildebrandt et al. 2009. PubMed ID: 19118152).

Primary Ciliary Dyskinesia

Primary Ciliary Dyskinesia (PCD) is a genetic disorder affecting the function of motile cilia (Leigh et al. 2009. PubMed ID: 19606528). The hallmark features of PCD are neonatal respiratory distress, chronic coughing, and recurrent sinus and/or ear infections; 80-100% of all PCD patients have one or more of these symptoms. In 20-50% of individuals with PCD, the major visceral organs are reversed from their normal positions (situs inversus) (Sutherland and Ware 2009. PubMed ID: 19876930). Kartagener’s syndrome is a condition defined by the symptomatic triad of situs inversus, sinusitis and bronchiectasis. Patients with PCD can also have abnormal orientation of some organs but not others (a condition called situs ambiguus or heterotaxy) (Kennedy et al. 2007. PubMed ID: 17515466). For more information, see GeneReviews (Zariwala et al. 2019. PubMed ID: 20301301).

Heterotaxy, Situs Inversus and Kartagener's syndrome

Primary Ciliary Dyskinesia (PCD) is a genetically heterogeneous disorder affecting the function of motile cilia (Leigh et al. 2009. PubMed ID: 19606528). The hallmark features of PCD are neonatal respiratory distress, chronic coughing, and recurrent sinus and/or ear infections; 80-100% of all PCD patients have one or more of these symptoms. In 20-50% of individuals with PCD, the major visceral organs are reversed from their normal positions, also called situs inversus (Sutherland and Ware 2009. PubMed ID: 19876930). Kartagener’s syndrome is a condition defined by the symptomatic triad of situs inversus, sinusitis and bronchiectasis. Patients with PCD can also have abnormal orientation of some organs but not others, a condition called situs ambiguus or heterotaxy (Kennedy et al. 2007. PubMed ID: 17515466). Heterotaxy syndrome results from a failure to properly establish left-right asymmetry during embryogenesis resulting in an abnormal arrangement of thoracic and/or abdominal visceral organs, including the heart, lungs, liver, spleen, intestines, and stomach. Affected patients frequently have significant morbidity and mortality due to a wide variety of cyanotic congenital heart defects. Common defects besides cardiac malformations include asplenia or polysplenia, left-sided liver, right-sided stomach, gastrointestinal malrotation, and altered lung lobation. Classic heterotaxy, cardiac malformations and visceral laterality defects, has an estimated prevalence of 1:10,000 live births (Lin et al. 2000. PubMed ID: 11256661).

The ciliopathy disorders described above have been proposed to represent a single clinical entity, with a spectrum of overlapping symptoms and causative genes.

Joubert and Meckel-Gruber Syndromes

JSRD and MKS are genetically heterogeneous; JSRD is known to be caused by pathogenic variants in at least 33 different genes and MKS is caused by pathogenic variants in at least 22 different genes (Hartill et al. 2017. PubMed ID: 29209597; Parisi et al. 2017. PubMed ID: 20301500; Knopp et al. 2015. PubMed ID: 26003401; Shaheen et al. 2016. PubMed ID: 27894351). Most of the genes reported to cause MKS have also been found to cause JSRD, with the exception of B9D2, KIF14, NPHP3, and TTC21B. In addition, all genes reported to cause MKS and JSRD play some role in the structure, function and maintenance of the primary cilia and/or basal body organelle (Hildebrandt et al. 2009. PubMed ID: 19118152). Thus, MKS and JSRD have been proposed to represent a single clinical entity, with a spectrum of overlapping symptoms and causative genes. JSRD and MKS are inherited in an autosomal recessive manner with the exception of OFD1, which is inherited in an X-linked dominant manner.

Bardet-Biedl Syndrome

BBS is a genetically heterogeneous disorder known to be caused by pathogenic variants in at least 25 different genes including ARL6/BBS3, BBIP1/BBS18, BBS1, BBS10, BBS12, BBS2, BBS4, BBS5, BBS7, BBS9, CEP164, CEP290/BBS14, C8orf37, IFT27/BBS19, IFT74/BBS20, IFT172, LZTFL1/BBS17, MKKS/BBS6, MKS1/BBS13, NPHP1, SDCCAG8/BBS16, TRIM32/BBS11, TTC8/BBS8, TTC21B, and WDPCP/BBS15 (Forsythe and Beales 2015. PubMed ID: 20301537; Leitch et al. 2008. PubMed ID: 18327255; Kim et al. 2010. PubMed ID: 20671153; Otto et al. 2010. PubMed ID: 20835237; Lindstrand et al. 2016. PubMed ID: 27486776; Heon et al. 2016. PubMed ID: 27008867; Bujakowska et al. 2015. PubMed ID: 25168386; Lindstrand et al. 2014. PubMed ID: 24746959). TMEM67 is included in this panel as it has been suggested to be a genetic modifier of the BBS phenotype (Leitch et al. 2008. PubMed ID: 18327255). BBS is marked by both intra- and inter-familial phenotypic variability. It has been suggested that BBS has an oligogenic inheritance pattern. Triallelism hypothesis states that three pathogenic alleles in two loci are necessary for BBS. This hypothesis attempts to explain variable expressivity and the observation that several individuals with BBS have been found to have a third rare, possibly pathogenic variant in a second BBS gene (Katsanis et al. 2001. PubMed ID: 11567139; Katsanis. 2004. PubMed ID: 14976158; Leitch et al. 2008. PubMed ID: 18327255). However, others have not found evidence for triallelic inheritance patterns in their cohorts (Smaoui et al. 2006. PubMed ID: 16877420; Abu-Safieh et al. 2012. PubMed ID: 22353939). In the majority of reported cases two pathogenic variants in one gene are sufficient for BBS. However, the severity may be modulated by an additional hypomorphic or loss of function allele(s) at another locus. It is recommended to use an autosomal recessive inheritance model when counseling patients and their families (Forsythe and Beales 2015. PubMed ID: 20301537).

Nephronophthisis and Senior-Loken syndrome

Nephronophthisis and Senior-Loken syndrome are genetically heterogeneous disorders. NPH and SLS are inherited in an autosomal recessive manner. NPH and SLS are caused by pathogenic variants in genes encoding proteins involved in cilia/centrosome structure, maintenance or function (Hildebrandt et al. 2009. PubMed ID: 19118152).

Primary Ciliary Dyskinesia Heterotaxy

Primary Ciliary Dyskinesia is caused by defects in motile cilia. Planar motion cilia (i.e. from the respiratory tract, brain, and reproductive tract) consist of nine microtubule doublets that surround a central core of two microtubules (9+2 configuration). Rotary motion cilia (i.e. those in the embryonal node) lack the central core microtubules (9+0 configuration). All motile cilia have inner and outer dynein arms attached at regular intervals to the nine peripheral microtubule doublets, which serve as molecular motors that drive microtubule sliding. For 9+2 cilia, radial spokes form a signal-transduction scaffold between the peripheral dynein arms and the central-core microtubule pair, giving these cilia their characteristic planar (i.e. forward and backward) motion. Motile cilia are very complex structures composed of roughly 250 proteins (Ferkol and Leigh 2006. PubMed ID: 17142159). To date, defects in over 40 genes have been reported to cause PCD, which is most commonly inherited in an autosomal recessive manner (Zariwala et al. 2019. PubMed ID: 20301301). Rarely, PCD has been found to be inherited in an X-linked manner due to loss-of-function variants in OFD1 or RPGR (Budny et al. 2006. PubMed ID: 16783569; Moore et al 2006. PubMed ID: 16055928). In addition, the INVS/NPHP2 gene has been associated with situs inversus either with or without biliary complications (Schon et al. 2002. PubMed ID: 11935322; Otto et al. 2003. PubMed ID: 12872123). Symptoms of cystic fibrosis can sometimes mimic those of PCD.

Heterotaxy, Situs Inversus and Kartagener's syndrome

Both PCD and heterotaxy are genetically heterogeneous. PCD can be caused by pathogenic variants in at least 39 genes and heterotaxy is caused by pathogenic variants in at least 9 genes (Zariwala et al. 2019. PubMed ID: 20301301). In addition, the INVS/NPHP2, ANKS6, PKD1L1, DNAH6, and DNAH9 genes have been associated with situs inversus or heterotaxy, either with or without biliary complications (Schon et al. 2002. PubMed ID: 11935322; Otto et al. 2003. PubMed ID: 12872123; Hoff et al. 2013. PubMed ID: 23793029; Vetrini et al. 2016. PubMed ID: 27616478; Li et al. 2016. PubMed ID: 26918822; Fassad. 2018. PubMed ID: 30471717). Thus, a common thread among all these genes is the association of laterality defects. ACVR2B, FOXH1, LEFTY2, NKX2-5 and NODAL genes are associated with autosomal dominant laterality defects, ZIC3 is associated with X-linked recessive heterotaxy, and AK7, ARMC4, ANKS6, CCDC103, CCDC114, CCDC39, CCDC40, CCDC151, CFAP53, CFAP298, DNAAF1, DNAAF2, DNAAF3, DNAAF5 (HEATR2), DNAI1, DNAI2, DNAH5, DNAH11, DNAL1, DNAAF4 (previously called DYX1C1), GAS8, INVS, LRRC6, MMP21, NME8, SPAG1, TTC25 and ZMYND10 are associated with autosomal recessive PCD with and without laterality defects. Heterozygous nonsense and missense variants in GDF1 were identified in individuals with conotruncal heart defects (TOF, DORV, TGA) without visceral laterality defects (Karkera et al. 2007. PubMed ID: 17924340). Two truncating variants in GDF1 were found to cause classic heterotaxy in one Finnish family with heterozygous carriers being asymptomatic (Kaasinen et al. 2010. PubMed ID: 20413652).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 98.4% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Clinical sensitivity for BBS is ~80% (Forsythe and Beales. 2015. PubMed ID: 20301537; Lindstrand et al. 2016. PubMed ID: 27486776).

Clinical sensitivity for Joubert syndrome and related disorders is 62%-94% (Parisi and Glass. 2017. PubMed ID: 20301500) and 50%-77% for Meckel-Gruber syndrome (Knopp et al. 2015. PubMed ID: 26003401; Hartill et al. 2017. PubMed ID: 29209597).

Clinical sensitivity for nephronophthisis is approximately 30% overall (Hildebrandt et al. 2009. PubMed ID: 19118152). Approximately 20% of individuals with nephronophthisis have a homozygous deletion encompassing the NPHP1 gene (Hoefele et al 2005. PubMed ID: 15776426; Hildebrandt et al 2009. PubMed ID: 19118152). This NGS test can detect the ~279 kb common NPHP1 deletion.

Clinical sensitivity for PCD is ~80% (Zariwala et al. 2019. PubMed ID: 20301301).