Table 4

Genotypes and phenotypes of 24 patients carry a single heterozygous variant/mutation in at least one of 11 nephronophthisis associated ciliopathies (NPHP-AC) genes

PatientDiagnosisOriginConsanguinityGeneNucleotide change* (zygosity)Amino acid changeMutant allele frequencyEvolutionary conservationPolyPhen-2 scoreMutation assignmentReference
D rerioC intestC elegans
F437-22NPHPItalyNPHP3c.3422T→C (h)p.L1141P78/5161 (1.5%)++0.996Dir.seq8
F299-22NPHP, LFGermanyNPHP4c.271T→C (h)p.F91L101/5196 (1.9%)+++0.998CEL I neg.41
F521-21JBTSArab+NPHP4c.944G→A (h)p.T315M244/6468 (3.8%)0.980CEL INovel
A396-21NPHPTurkey+IQCB1c.1271A→G (h)p.Q424R227/13809 (1.6%)++0.980CEL INovel
A75-21§NPHPPolandndCEP290c.254A→C (h)p.N85T13/1487 (0.9%)+0.995CEL INovel
F631-21JBTSGermanyRPGRIP1Lc.1177G→A (h)p.E393K115/6747 (1.7%)+0.980CEL I42
A75-21§NPHPPolandndRPGRIP1Lc.1964A→G (h)p.Y655C191/12672 (1.5%)+1.000CEL INovel
A1042-21JBTSGermanyTMEM67c.1334T→C (h)p.V445A135/6734 (2.0%)+0.992CEL INovel
A108-22JBTSNDndTMEM67c.1911C→T (h)p.F637LNA+0.999Dir.seqNovel
A380-21SLSNItaly+TMEM67c.2009C→T (h)p.T670I421/15859 (2.7%)++0.992CEL I neg.Novel
F962-23¶NPHP, NPHP4SwissndTMEM67c.2374A→G (h)p.R792G37/3058 (1.2%)+++1.000CEL I neg.Novel
A386-21JBTSTurkeyTMEM67c.2461G→A (h)p.G821SNA+++0.980Dir.seq14
A1421-21§JBTSEgyptTMEM67c.2461G→A (h)p.G821S98/4402 (2.2%)+++0.980CEL I14
A805-21NPHPPakistan+ARL13Bc.1169G→A (h)p.R390LNA+0.993Dir.seqNovel
F459-22JBTS, TMEM67USAndCC2D2Ac.1519A→G (h)p.K507E154/5654 (2.7%)+0.780CEL INovel
F16-21SLSNFranceCC2D2Ac.1519A→G (h)p.K507E154/5654 (2.7%)+0.780CEL INovel
A3208-21JBTSUKCC2D2Ac.1519A→G (h)p.K507E61/3307 (1.8%)+0.780CEL INovel
A559-22NPHPArab+CC2D2Ac.2161C→T (h)p.P721S122/7296 (1.7%)++0.999CEL I neg.39
A944-21NPHPPakistani+CC2D2Ac.2161C→T (h)p.P721S383/9355 (4.1%)++0.999CEL I39
A1347-21NPHPTurkey+CC2D2Ac.2161C→T (h)p.P721S383/9355 (4.1%)++0.999CEL I39
A1421-21§JBTSEgyptCC2D2Ac.3056G→A (h)p.R1019Q272/11649 (2.3%)+++1.000CEL INovel
A1152-21SLSNArabTTC21Bc.2258C→T (h)p.P753L24/1534 (1.6%)++0.999CEL INovel
A2430-21MKSUKTTC21Bc.2588G→A (h)p.R863Q35/1016 (3.4%)++0.733CEL INovel
A1502-21JBTSUSATTC21Bc.3004C→G (h)p.L1002V125/6667 (1.9%)++0.922CEL INovel
F132-24NPHPUSAMKS1c.857T→C (h)p.D286G156/6617 (2.4%)+0.983CEL INovel
A1859-21JBTSAustriaXPNPEP3c.463C→T (h)p.R155W99/5373 (1.8%)++0.907CEL INovel
  • * All mutations were absent from 96 healthy control subjects. Direct Sanger sequencing for all exons in the respective gene was performed in order to identify a second mutated allele but was negative. Mutation numbering is based on cDNA position in reference sequences indicated in table 1 with +1 corresponding to the A of the ATG translation initiation codon.

  • PolyPhen-2 (Polymorphism Phenotyping v2) is a tool which predicts possible impact of an amino acid substitution on the structure and function of a human protein using straightforward physical and comparative considerations ( Scores were given between 0 (benign) and 1 (possibly damaging). We analysed only missense changes with PolyPhen scores above 0.7.

  • The mutation carrier assignment (from a pool of 24) was performed by heteroduplex based CEL I endonuclease screening (CEL I) or by direct Sanger sequencing of all 24 DNA samples (Dir. Seq) for the respective exon. In cases where CEL I analysis was inconclusive or negative (CEL I neg.), all 24 DNA samples from the respective DNA pool were directly sequenced.

  • § Patients A75-21 and A1421-21 carry heterozygous variants/mutations in two different NPHP-AC genes.

  • Patient F962 carries a compound heterozygous mutation in NPHP4.

  • (h), heterozygous; inf., infantile; JBTS, Joubert syndrome; NPHP, nephronophthisis; MKS, Meckel–Gruber syndrome; nd, no data; C intest, Ciona intestinalis; D rerio, Danio rerio; C elegans, Caenorhabditis elegans.