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    Cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140 and confirms a Mainzer–Saldino syndrome diagnosis
    1
    1. ClingenBaseline 21 Oct 2026
      Cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140 and confirms a Mainzer–Saldino syndrome diagnosis

      PMID: 30479745

      Gene: IFT140

      HGNC: 29077

      Disease: Short-rib thoracic dysplasia 9 with or without polydactyly

      MONDO: 0009964

      InheritancePattern: autosomal recessive

      Prevalence: Within the lumped disease entity for this curation, the most prevalent form may be retinitis pigmentosa. The prevalence of Saldino-Mainzer syndrome (one of the synonyms of Short-rib thoracic dysplasia 9) is less than 1 in 1,000,000. The prevalence of Leber congenital amaurosis cases caused by IFT140 variants (PMID: 26216056) is calculated to be less than 1 in 3,000,000. Although IFT140 variants are estimated to be responsible for less than 2% of RP, the prevalence of the overall disorder at 1 in 3,000 or 1 in 4,000 means the frequency of these cases could potentially be higher than 1 in 1,000,000.

      Penetrance: Known variants for this lumped disease entity appear to be completely penetrant, with highly variable phenotypes and age of onset. On the other hand, the split disease entity caused by monoallelic IFT140 variants appears to have incomplete penetrance.

      General ClinGen Gene:IFT140 HGNC:29077 inferred_gene_hgnc:29077 inferred_gene_source:hgnc_tag Retina GCEP
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    ncbi.nlm.nih.gov/pmc/articles/PMC6247778/
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    Mutations in human IFT140 cause non-syndromic retinal degeneration
    3
    1. ClingenBaseline 21 Oct 2026
      The other patient, SRF92, is an 11-year-old male diagnosed with LCA/early onset severe retinal dystrophy. His fundus image showed extensive retinal pigment crumbs including macula region and OCT results indicated IS/OS loss and retinal atrophy (Fig. 1). According to Sanger sequencing, this patient inherited a frameshift variant (c.1655_1656delAG, p.E522Gfs*6) from his father and a missense variant (c.G2368A, p.E790K) from his mother (Fig. 2). Both variants are extremely rare in control individuals (less than 1 in 60,000). Similar to previously described variants, the E790 K variant affects a conserved AA site and predicted to be damaging by five out of six algorithms. This patient also does not show typical MZSDS or JATD-like syndromic phenotypes but has hypogonadism and mild fatty liver disease (Table 1, Table S3).

      Case#: Xu_2012_Patient_SRF92, male, 11 years of age at time of study, of Chinese ethnicity

      CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000556 (Retinal dystrophy), HP:0000580 (Pigmentary retinopathy), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0001105 (Retinal atrophy), HP:0000026 (Male hypogonadism)

      CaseHPOFreeText: This proband was diagnosed with Leber congenital amaurosis, and has mild fatty liver disease.

      CaseNotHPOs: HP:0000924 (Abnormality of the skeletal system), HP:0000077 (Abnormality of the kidney)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: It is not clear whether the patient was previously subjected to genotyping.

      CaseMethod1: Whole exome sequencing

      CaseMethod2: Sanger sequencing of IFT140

      CaseGenotypingMethod: The patient and family members were genotyped by whole exome sequencing and confirmed by Sanger sequencing of IFT140.

      Variant: The patient is a compound heterozygote harboring the paternal NM_014714.3(IFT140):c.1655_1656del (p.Glu522Glyfs6) and maternal NM_014714.3(IFT140):c.2368G>A (p.Glu790Lys) variants in IFT140*.

      CAID: CA2201732453, CA7813927

      gnomAD: The NM_014714.3(IFT140):c.1655_1656del (p.Glu522Glyfs*6) variant was not found in gnomAD. The NM_014714.3(IFT140):c.2368G>A (p.Glu790Lys) variant is present in gnomAD at a frequency of 0.0001087 in the East Asian population (2/18394, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1607967-C-T

      VariantEvidence: NM_014714.3(IFT140):c.1655_1656del (p.Glu522Glyfs*6) is a frameshift variant that introduces a premature stop codon in exon 15/31 and is predicted to trigger NMD or at least to truncate ~64% of the protein product. NM_014714.3(IFT140):c.2368G>A (p.Glu790Lys) is a missense variant that does not have functional evidence of gene impact.

      CaseAddInfo: The proband's parents are each heterozygous for one variant.

      CasePMIDs: N/A

      Case Individual CaseInfo Gene:IFT140 HGNC:29077 inferred_gene_hgnc:29077 inferred_gene_source:hgnc_tag Retina GCEP
    2. ClingenBaseline 21 Oct 2026
      The index case we investigated, SRF71, is a 43-year-old male RP patient of Han Chinese ethnicity. He was aware of night blindness during childhood and vision loss at the age of 36 (Table 1). His fundus images showed widespread retinal bone spicule pigmentation, and gold foil macular reflex. OCT images showed loss of inner segment (IS)/outer segment (OS) of photoreceptor cells (Fig. 1). His parents are normal and he has an unaffected sister. Preliminary screening by retinal capture sequencing found no causative mutations in known RP-causing genes. WES data show that he has biallelic variants in IFT140, including a missense (c.T4196C, p. L1399P) and a frameshift (c. 1898_1901delATAA, p. N633Sfs*10) variant. Neither variant was found more than once in ExAC controls (Table 1). The missense variant disrupts a highly conserved amino acid (AA) in TPR9 domain and is considered to be damaging by 5 out of 6 prediction algorithms (Fig. 3; Table S2). The frameshift variant does not lie in the last exon thus it probably leads to a nonsense-mediated decay of the IFT140 transcript. Sanger sequencing confirmed his unaffected sister is wild type at these two alleles and his parents possess one IFT140 variant each, supporting the pathogenicity of the IFT140 variants (Fig. 2). Given that IFT140 is associated with syndromic ciliopathies, we performed radiography of skeletons and laboratory tests for hepatic and renal functions. Interestingly, the patient does not show any other symptoms or abnormalities after detailed examination (Figure S4, Table S3). Therefore, these results raise the possibility that mutations in IFT140 might lead to non-syndromic retinal disease.

      Case#: Xu_2012_Patient_SRF71, male, 43 years of age at time of study, of Han Chinese ethnicity

      CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000662 (Nyctalopia), HP:0000572 (Visual loss), HP:0007737 (Bone spicule pigmentation of the retina), HP:0030609 (Photoreceptor layer loss on macular OCT)

      CaseHPOFreeText: This proband was diagnosed with retinitis pigmentosa.

      CaseNotHPOs: HP:0000924 (Abnormality of the skeletal system), HP:0001410 (Decreased liver function), HP:0000077 (Abnormality of the kidney)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: The patient was previously subjected to retinal capture sequencing focused on genes known to be associated with retinitis pigmentosa, without detecting suspected pathogenic variants.

      CaseMethod1: Whole exome sequencing

      CaseMethod2: Sanger sequencing of IFT140

      CaseGenotypingMethod: Following the failure of retinal capture sequencing to identify retinitis pigmentosa gene variants, the patient and family members were genotyped by whole exome sequencing and confirmed by Sanger sequencing of IFT140.

      Variant: The patient is a compound heterozygote harboring the paternal NM_014714.4(IFT140):c.1898_1901del (p.Asn633fs) and maternal NM_014714.4(IFT140):c.4196T>C (p.Leu1399Pro) variants in IFT140.

      ClinVar: 446312, 446311

      gnomAD: The NM_014714.4(IFT140):c.1898_1901del (p.Asn633fs) variant was not found in gnomAD. The NM_014714.4(IFT140):c.4196T>C (p.Leu1399Pro) variant is present in gnomAD at a frequency of 0.0001578 in the East Asian population (3/19014, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1561138-A-G

      VariantEvidence: NM_014714.4(IFT140):c.1898_1901del (p.Asn633fs) is a frameshift variant that introduces a premature stop codon in exon 16/31 and is predicted to trigger NMD or at least to truncate ~57% of the protein product. NM_014714.4(IFT140):c.4196T>C (p.Leu1399Pro) is a missense variant that does not have functional evidence of gene impact.

      CaseAddInfo: The proband's parents are each heterozygous for one variant, while his unaffected sister does not harbor a variant.

      CasePMIDs: N/A

      Case Individual CaseInfo Gene:IFT140 HGNC:29077 inferred_gene_hgnc:29077 inferred_gene_source:hgnc_tag Retina GCEP
    3. ClingenBaseline 21 Oct 2026
      Mutations in human IFT140 cause non-syndromic retinal degeneration

      PMID: 26216056

      Gene: IFT140

      HGNC: 29077

      Disease: Short-rib thoracic dysplasia 9 with or without polydactyly

      MONDO: 0009964

      InheritancePattern: autosomal recessive

      Prevalence: Within the lumped disease entity for this curation, the most prevalent form may be retinitis pigmentosa. The prevalence of Saldino-Mainzer syndrome (one of the synonyms of Short-rib thoracic dysplasia 9) is less than 1 in 1,000,000. The prevalence of Leber congenital amaurosis cases caused by IFT140 variants (PMID: 26216056) is calculated to be less than 1 in 3,000,000. Although IFT140 variants are estimated to be responsible for less than 2% of RP, the prevalence of the overall disorder at 1 in 3,000 or 1 in 4,000 means the frequency of these cases could potentially be higher than 1 in 1,000,000.

      Penetrance: Known variants for this lumped disease entity appear to be completely penetrant, with highly variable phenotypes and age of onset. On the other hand, the split disease entity caused by monoallelic IFT140 variants appears to have incomplete penetrance.

      General ClinGen Gene:IFT140 HGNC:29077 inferred_gene_hgnc:29077 inferred_gene_source:hgnc_tag Retina GCEP
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    link.springer.com/article/10.1007/s00439-015-1586-x
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    TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia
    1
    1. ClingenBaseline 21 Oct 2026
      TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia

      PMID: 20889716

      Gene: IFT140

      HGNC: 29077

      Disease: Short-rib thoracic dysplasia 9 with or without polydactyly

      MONDO: 0009964

      InheritancePattern: autosomal recessive

      Prevalence: Within the lumped disease entity for this curation, the most prevalent form may be retinitis pigmentosa. The prevalence of Saldino-Mainzer syndrome (one of the synonyms of Short-rib thoracic dysplasia 9) is less than 1 in 1,000,000. The prevalence of Leber congenital amaurosis cases caused by IFT140 variants (PMID: 26216056) is calculated to be less than 1 in 3,000,000. Although IFT140 variants are estimated to be responsible for less than 2% of RP, the prevalence of the overall disorder at 1 in 3,000 or 1 in 4,000 means the frequency of these cases could potentially be higher than 1 in 1,000,000.

      Penetrance: Known variants for this lumped disease entity appear to be completely penetrant, with highly variable phenotypes and age of onset. On the other hand, the split disease entity caused by monoallelic IFT140 variants appears to have incomplete penetrance.

      General ClinGen Gene:IFT140 HGNC:29077 inferred_gene_hgnc:29077 inferred_gene_source:hgnc_tag Retina GCEP
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    ncbi.nlm.nih.gov/pmc/articles/PMC2947770/