PMID: 29706353

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.

ExperimentName: Rescue in patient-derived IPSC cells harboring IFT140 variants

RescueProband: Forbes_2018_Proband_1 has been diagnosed with retinitis pigmentosa (age 1), end-stage kidney disease (age 6), and Mainzer-Saldino syndrome (at the time of this study). The proband and her non-consanguineous parents were genotyped by Trio whole exome sequencing, identifying compound heterozygous (paternal and maternal) IFT140 variants in the proband.

GeneAlteration: The proband harbors the NM_014714.4(IFT140):c.634G>A (p.Gly212Arg) and NM_014714.4(IFT140):c.2176C>G (p.Pro726Ala) variants in trans. The former variant has been shown to mislocalize when exogenously expressed as a cDNA, and is predicted to disrupt a donor splice site (SpliceAI change score of 0.61).

RescueVariant: The variant rescued by CRISPR/Cas9-based gene editing was NM_014714.4(IFT140):c.634G>A (p.Gly212Arg), (ClinVar ID: 31683). This variant was corrected at the same time as a synonymous 3 bp change was introduced to facilitate the detection of the editing event.

RescuedPhenotype: Patient IPSC-derived organoids exhibit Short / clubbed cilia with swollen sips (Figure 3A-3C), Approximately 50% expression of IFT140 at both the mRNA and protein levels (Figures 2D, 2E), and Disturbed apicobasal polarity compromising the ability of iPSC cells to establish polarized spheroids (Figures 5C, 5D).

RescueMethod: CRISPR/Cas9-based gene editing was used to correct one of the proband's two variants (NM_014714.4(IFT140):c.634G>A (p.Gly212Arg), (ClinVar ID: 31683)). A synonymous 3 bp change was simultaneously introduced to facilitate the detection of the editing event.

RescueEvidence: Gene-corrected cells had longer ciliary length with reduced clubbing (Figure 3), approximately twice the expression of IFT140 at the mRNA and protein levels (Figures 2D, 2E), and a higher percentage of polarized spheroids established in organoid culture (indicating recovery of apicobasal polarity).

Case#: Perrault_2012_Patient_FVII1, male, 18 months of age at time of study, ethnicity not specified

CasePresentingHPOs: HP:0001252 (Hypotonia), HP:0011968 (Feeding difficulties), HP:0003577 (Congenital onset), HP:0000639 (Nystagmus), HP:0010306 (Short thorax), HP:0000773 (Short ribs), HP:0010230 (Cone-shaped epiphyses of the phalanges of the hand), HP:0000093 (Proteinuria), HP:0001970 (Tubulointerstitial nephritis), HP:0004719 (Hyperechogenic kidneys)

CaseHPOFreeText: This proband was diagnosed with Jeune syndrome, unlike the other probands in this study who were diagnosed with Mainzer-Saldino syndrome. Limbs are described as trident. Elevated urea listed as a kidney-related phenotype.

CaseNotHPOs: HP:0025404 (Abnormal visual fixation), HP:0004322 (Short stature), HP:0000929 (Abnormal skull morphology)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes)

CaseMethod2: Sanger sequencing of the 29 coding exons of IFT140

CaseGenotypingMethod: The patient was genotyped by ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes), confirmed by Sanger sequencing of the 29 coding exons of IFT140

Variant: The patient is a compound heterozygote harboring the NM_014714.4(IFT140):c.634G>A (p.Gly212Arg) and NM_014714.4(IFT140):c.2399+1G>T variants in IFT140.

ClinVar: 31683, 31680

gnomAD: The NM_014714.4(IFT140):c.634G>A (p.Gly212Arg) variant is present in gnomAD at a frequency of 0.00009295 in the European (non-Finnish) population (12/129100, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1642177-C-T The NM_014714.4(IFT140):c.2399+1G>T variant is present in gnomAD at a frequency of 0.0001231 in the European (non-Finnish) population (14/113764, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1607935-C-A

VariantEvidence: Exogenous expression of the FLAG-tagged p.Gly212Arg variant in the RPE1 (retinal pigment epithelial) cell line revealed an inability to co-localize with gamma-tubulin, indicating a defect in localization to the basal body in most cells that is less severe than one of the other suspected pathogenic missense variants (Figure 3A). The NM_014714.4(IFT140):c.2399+1G>T variant disrupts a canonical splice donor site and is predicted but not confirmed to trigger skipping of exon 18/31.

CaseAddInfo: The proband's parents are reportedly non-consanguineous.

CasePMIDs: N/A

FamilyLabel: Perrault_2012_Family_FIV

Family#PresentingHPOs: HP:0003593 (Infantile onset), HP:0000639 (Nystagmus), HP:0007663 (Reduced visual acuity)

Family#PresentingHPOFreeText: Staining of ciliary axonemes for acetylated alpha-tubulin detected an absence of cilia in a high percentage of cultured fibroblast cells, relative to control patients. Affected family members have been diagnosed with Mainzer-Saldino syndrome.

FamilyNotHPOs: HP:0001410 (Decreased liver function), HP:0012211 (Abnormal renal physiology)

FamilyNotHPOFreeText: IFT140 protein localization along the ciliary axoneme was unaffected in patient FIV3, however, two components of the anterograde transport IFT-B complex, IFT88 and IFT46, were aberrantly localized. They were evenly distributed along the cilium instead of primarily localized at the base and the tip of the cilium, suggesting an alteration in retrograde ciliary transport.

CountryOrigin: Saudi Arabia

Ethnicity: Not described.

Race: Not described.

Family#PreviousTesting: N/A

FamilyMethod1: Ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes)

Family#Method2: Sanger sequencing of the 29 coding exons of IFT140.

Family#GenotypingMethod: The family was genotyped by ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes), confirmed by Sanger sequencing of the 29 coding exons of IFT140

Affected: 3

Unaffected: 3

Segregations: 2 segregation were reported. The pedigree can be found in Figure S1. The family was described as consanguineous.

PublishedLOD: N/A

eLOD: 1.50

AddSegregationInfo: N/A

ProbandLabel: Perrault_2012_patient_FIV3

Variant: Affected individuals harbor the NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) variant in a homozygous state.

ClinVar: 31679

gnomAD: The NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) variant is present in gnomAD at a frequency of 0.00004031 in the African / African-American population (1/24806, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1614075-C-T

FamilyAddInfo: The parents of the affected family members are reportedly consanguineous (first cousins).

FamilyPMIDs: N/A

Case#: Perrault_2012_Patient_FII1, male, 18 years of age at time of study, ethnicity not specified

CasePresentingHPOs: HP:0003577 (Congenital onset), HP:0000639 (Nystagmus), HP:0025573 (Mild myopia), HP:0007994 (Peripheral visual field loss), HP:0007663 (Reduced visual acuity), HP:0007814 (Retinal pigment epithelial mottling), HP:0000608 (Macular degeneration), HP:0000550 (Undetectable electroretinogram), HP:0010164 (Cone-shaped epiphyses of the toes), HP:0003774 (Stage 5 chronic kidney disease), HP:0002153 (Hyperkalemia), HP:0000113 (Polycystic kidney dysplasia), HP:0000556 (Retinal dystrophy), HP:0001396 (Cholestasis), HP:0010230 (Cone-shaped epiphyses of the phalanges of the hand)

CaseHPOFreeText: Photoattraction was listed as a phenotype. Acetylated alpha-tubulin staining in cultured fibroblasts showed an absence of primary cilia in a high number of cells from this patient.

CaseNotHPOs: HP:0004322 (Short stature), HP:0000773 (Short ribs), HP:0000900 (Thickened ribs), HP:0000929 (Abnormal skull morphology), HP:0040064 (Abnormality of limbs), HP:0001263 (Global developmental delay), HP:0004979 (Metaphyseal sclerosis)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes)

CaseMethod2: Sanger sequencing of the 29 coding exons of IFT140

CaseGenotypingMethod: The patient was genotyped by ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes), confirmed by Sanger sequencing of the 29 coding exons of IFT140

Variant: The patient is a compound heterozygote harboring the NM_014714.4(IFT140):c.932A>G (p.Tyr311Cys) and NM_014714.4(IFT140):c.857_860del (p.Ile286LysfsTer6) variants in IFT140.

ClinVar: 31681

CAID: CA129888

gnomAD: Neither variant was found in gnomAD.

VariantEvidence: Exogenous expression of the FLAG-tagged p.Tyr311Cys variant in the RPE1 (retinal pigment epithelial) cell line revealed an inability to co-localize with gamma-tubulin, indicating a defect in localization to the basal body in most cells, although milder than another suspected pathogenic missense variant (Figure 3A). The p.Ile286LysfsTer6) variant is a frameshift variant in exon 8 of 31, introducing a premature stop codon predicted to trigger nonsense-mediated decay or at least disrupt the C-terminal 81% of the protein product.

CaseAddInfo: The proband's parents are reportedly non-consanguineous.

CasePMIDs: N/A

PMID: 22503633

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.

Case#: Perrault_2012_Patient_FV1, male, 10 years of age at time of study, ethnicity not specified

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000545 (Myopia), HP:0007994 (Peripheral visual field loss), HP:0032037 (Mildly reduced visual acuity), HP:0000510 (Rod-cone dystrophy), HP:0000512 (Abnormal electroretinogram), HP:0004322 (Short stature), HP:0001363 (Craniosynostosis), HP:0030799 (Scaphocephaly), HP:0001999 (Abnormal facial shape), HP:0010230 (Cone-shaped epiphyses of the phalanges of the hand), HP:0000365 (Hearing impairment), HP:0003774 (Stage 5 chronic kidney disease), HP:0000107 (Renal cyst), HP:0004719 (Hyperechogenic kidneys), HP:0005565 (Reduced renal corticomedullary differentiation), HP:0001510 (Growth delay)

CaseHPOFreeText: This proband was diagnosed with Mainzer-Saldino syndrome.

CaseNotHPOs: HP:0000639 (Nystagmus)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes)

CaseMethod2: Sanger sequencing of the 29 coding exons of IFT140

CaseGenotypingMethod: The patient was genotyped by ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes), confirmed by Sanger sequencing of the 29 coding exons of IFT140

Variant: The patient is a compound heterozygote harboring the NM_014714.4(IFT140):c.634G>A (p.Gly212Arg) and NM_014714.4(IFT140):c.3916dup (p.Ala1306fs) variants in IFT140.

ClinVar: 31683, 31684

gnomAD: The NM_014714.4(IFT140):c.634G>A (p.Gly212Arg) variant is present in gnomAD at a frequency of 0.00009295 in the European (non-Finnish) population (12/129100, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1642177-C-T The NM_014714.4(IFT140):c.3916dup (p.Ala1306fs) variant is present in gnomAD at a frequency of 0.0001210 in the African / African-American population (3/24790, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1570005-G-GC

VariantEvidence: Exogenous expression of the FLAG-tagged p.Gly212Arg variant in the RPE1 (retinal pigment epithelial) cell line revealed an inability to co-localize with gamma-tubulin, indicating a defect in localization to the basal body in most cells that is less severe than one of the other suspected pathogenic missense variants (Figure 3A). NM_014714.4(IFT140):c.3916dup (p.Ala1306fs) is a frameshift variant that introduces a premature stop codon in exon 28/31 and is predicted to trigger NMD or at least to truncate ~11% of the protein product.

CaseAddInfo: The proband's parents are reportedly non-consanguineous.

CasePMIDs: N/A

Case#: Perrault_2012_Patient_FIV3, male, 17 years of age at time of study, Saudi Arabian national origin

CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0000639 (Nystagmus), HP:0000729 (Autistic behavior), HP:0001250 (Seizure), HP:0008499 (High hypermetropia), HP:0001123 (Visual field defect), HP:0007663 (Reduced visual acuity), HP:0000550 (Undetectable electroretinogram), HP:0010230 (Cone-shaped epiphyses of the phalanges of the hand), HP:0000556 (Retinal dystrophy)

CaseHPOFreeText: Acetylated alpha-tubulin staining in cultured fibroblasts showed an absence of primary cilia in a high number of cells from this patient. IFT140 protein localization along the ciliary axoneme was unaffected, however, two components of the anterograde transport IFT-B complex, IFT88 and IFT46, were aberrantly localized. They were evenly distributed along the cilium instead of primarily localized at the base and the tip of the cilium, suggesting an alteration in retrograde ciliary transport.

CaseNotHPOs: HP:0004322 (Short stature), HP:0000765 (Abnormal thorax morphology), HP:0000929 (Abnormal skull morphology), HP:0040064 (Abnormality of limbs), HP:0001410 (Decreased liver function), HP:0012211 (Abnormal renal physiology), HP:0003272 (Abnormal hip bone morphology)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes)

CaseMethod2: Sanger sequencing of the 29 coding exons of IFT140

CaseGenotypingMethod: The patient was genotyped by ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes), confirmed by Sanger sequencing of the 29 coding exons of IFT140

Variant: Affected individuals harbor the NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) variant in a homozygous state.

ClinVar: 31679

gnomAD: The NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) variant is present in gnomAD at a frequency of 0.00004031 in the African / African-American population (1/24806, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1614075-C-T

VariantEvidence: Exogenous expression of the FLAG-tagged p.Glu664Lys variant in the RPE1 (retinal pigment epithelial) cell line revealed an inability to co-localize with gamma-tubulin, indicating a relatively severe defect in localization to the basal body in most cells, relative to other suspected pathogenic missense variants and the wild-type control (Figure 3A).

CaseAddInfo: The proband's parents are reportedly consanguineous (first cousins).

CasePMIDs: N/A

Case#: Perrault_2012_Patient_FI1, male, 17 years of age at time of study, ethnicity not specified

CasePresentingHPOs: HP:0000774 (Narrow chest), HP:0030289 (Flattened femoral epiphysis), HP:0006429 (Broad femoral neck), HP:0004979 (Metaphyseal sclerosis), HP:0010230 (Cone-shaped epiphyses of the phalanges of the hand), HP:0003593 (Infantile onset), HP:0000639 (Nystagmus), HP:0008499 (High hypermetropia), HP:0030526 (Severe constriction of peripheral visual field), HP:0008043 (Retinal arteriolar constriction), HP:0000550 (Undetectable electroretinogram), HP:0004322 (Short stature), HP:0000773 (Short ribs), HP:0000900 (Thickened ribs), HP:0003774 (Stage 5 chronic kidney disease), HP:0000107 (Renal cyst), HP:0030532 (Visual acuity test abnormality), HP:0000556 (Retinal dystrophy)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002093 (Respiratory insufficiency), HP:0010454 (Acetabular spurs), HP:0001410 (Decreased liver function), HP:0000929 (Abnormal skull morphology), HP:0040064 (Abnormality of limbs), HP:0001263 (Global developmental delay)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes)

CaseMethod2: Sanger sequencing of the 29 coding exons of IFT140

CaseGenotypingMethod: The patient was genotyped by ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes), confirmed by Sanger sequencing of the 29 coding exons of IFT140

Variant: The patient is a compound heterozygote harboring the NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) and NM_014714.4(IFT140):c.2399+1G>T variants in IFT140.

ClinVar: 31679, 31680

gnomAD: The NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) variant is present in gnomAD at a frequency of 0.00004031 in the African / African-American population (1/24806, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1614075-C-T The NM_014714.4(IFT140):c.2399+1G>T variant is present in gnomAD at a frequency of 0.0001231 in the European (non-Finnish) population (14/113764, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1607935-C-A

VariantEvidence: Exogenous expression of the FLAG-tagged p.Glu664Lys variant in the RPE1 (retinal pigment epithelial) cell line revealed an inability to co-localize with gamma-tubulin, indicating a relatively severe defect in localization to the basal body in most cells, relative to other suspected pathogenic missense variants and the wild-type control (Figure 3A). The NM_014714.4(IFT140):c.2399+1G>T variant disrupts a canonical splice donor site and is predicted but not confirmed to trigger skipping of exon 18/31.

CaseAddInfo: The proband's parents are reportedly non-consanguineous.

CasePMIDs: N/A

Case#: Schmidts_2013_Patient_JATD1, male, 12 years of age at time of study, of Serbian ethnicity

CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0002093 (Respiratory insufficiency), HP:0000556 (Retinal dystrophy), HP:0009370 (Type A brachydactyly), HP:0004322 (Short stature), HP:0005257 (Thoracic hypoplasia), HP:0010579 (Cone-shaped epiphysis), HP:0000369 (Low-set ears), HP:0003774 (Stage 5 chronic kidney disease), HP:0007703 (Abnormality of retinal pigmentation), HP:0000803 (Renal cortical cysts), HP:0033130 (Abnormal renal echogenicity), HP:0000822 (Hypertension), HP:0000773 (Short ribs), HP:0000900 (Thickened ribs), HP:0000774 (Narrow chest)

CaseHPOFreeText: This proband was diagnosed with Jeune's asphyxiating thoracic dystrophy (JATD).

CaseNotHPOs: HP:0010442 (Polydactyly), HP:0001737 (Pancreatic cysts), HP:0001392 (Abnormality of the liver), HP:0001263 (Global developmental delay)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing appears to have been limited to a clinical diagnosis of Jeune's asphyxiating thoracic dystrophy.

CaseMethod1: Whole exome sequencing, focusing on variants consistent with autosomal recessive inheritance and homologous to genes present in the ciliary proteome.

CaseMethod2: Sanger sequencing of IFT140 in the patient and available family members

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_014714.4(IFT140):c.874G>A (p.Val292Met) and maternal NM_014714.4(IFT140):c.1380del (p.Asn460fs) variants in IFT140.

ClinVar ID: 97053, 97055

gnomAD: The NM_014714.4(IFT140):c.874G>A (p.Val292Met) variant is present in gnomAD at a frequency of 0.000008852 in the European non-Finnish population (1/112966, with no homozygotes). https://gnomad.broadinstitute.org/variant/16-1637962-C-T The NM_014714.4(IFT140):c.1380del (p.Asn460fs) variant is present in gnomAD at a frequency of 0.000008804 in the European non-Finnish population (1/113590, with no homozygotes). https://gnomad.broadinstitute.org/variant/16-1633366-CG-C

VariantEvidence: NM_014714.4(IFT140):c.874G>A (p.Val292Met) is a missense variant that does not have functional evidence of gene impact. NM_014714.4(IFT140):c.1380del (p.Asn460fs) is a frameshift variant that introduces a premature stop codon in exon 12/31 and is predicted to trigger NMD or at least to truncate ~69% of the protein product.

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

CasePMIDs: N/A

PMID: 23418020

Gene: IFT140

HGNC: 29077

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

MONDO: 0009964

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of short-rib thoracic dysplasia is estimated to be between 1 in 100,000 and 1 in 130,000 births (PMID: 931421).

Penetrance: Disease caused by biallelic IFT140 variants appears to be fully penetrant.

PMID: 26359340

Gene: IFT140

HGNC: 29077

Disease: Retinitis pigmentosa 80

MONDO: 0054708

InheritancePattern: autosomal recessive

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of Retinitis pigmentosa with a recessive mode of inheritance is estimated to be 65-85% (between 1 in 3,500 and 1 in 6,500).

Penetrance: Disease caused by biallelic IFT140 variants appears to be fully penetrant.

Case#: Bifari_2016_Patient_3, male, 1 year of age at time of onset, of Saudi ethnicity

CasePresentingHPOs: HP:0003577 (Congenital onset), HP:0000505 (Visual impairment), HP:0000639 (Nystagmus), HP:0040082 (Happy demeanor), HP:0012758 (Neurodevelopmental delay), HP:0001483 (Eye poking), HP:0031729 (Moderate hypermetropia), HP:0025404 (Abnormal visual fixation), HP:0000550 (Undetectable electroretinogram), HP:0000556 (Retinal dystrophy)

CaseHPOFreeText: This proband exhibited photophilia / staring at lights.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

PMID: 24009529

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.

ExperimentName: Mouse homozygous mutant model of partial IFT140 loss-of-function

NonHumanModel: Mus musculus

GeneAlteration: The Cauli mouse model has biallelic disruption of the mouse Ift140 gene introduced by mutagenesis using N-ethyl-N-nitrosourea. The mutation is a missense change is c.2564T>A (p.Ile855Lys) in Ift140.

ModelPhenotype: HP:0034241 (Prenatal death), HP:0030769 (Exencephaly), HP:0002414 (Spina bifida), HP:0001999 (Abnormal facial shape), HP:0002648 (Abnormality of calvarial morphology), HP:0011297 (Abnormal digit morphology), HP:0001627 (Abnormal heart morphology), HP:0033334 (Abnormal embryonic development, specifically defects in somite patterning), HP:0000528 (Anophthalmia), HP:0001829 (Foot polydactyly), HP:0000194 (Open mouth), HP:0000772 (Abnormal rib morphology), HP:0000896 (Rib exostoses), HP:0001789 (Hydrops fetalis), HP:0001654 (Abnormal heart valve morphology), HP:0010290 (Short hard palate),

HumanPhenotype: HP:0001156 (Brachydactyly), HP:0010579 (Cone-shaped epiphysis), HP:0000556 (Retinal dystrophy), HP:0001591 (Bell-shaped thorax), HP:0000773 (Short ribs), HP:0000107 (Renal cyst), HP:0001252 (Hypotonia), HP:0001263 (Global developmental delay), HP:0001363 (Craniosynostosis), HP:0005054 (Metaphyseal spurs), HP:0010454 (Acetabular spurs), HP:0000083 (Renal insufficiency), HP:0002093 (Respiratory insufficiency), absent cilia in fibroblasts

ModelEvidence: The mode of inheritance in this model matches the biallelic/homozygous mode of inheritance observed in human disease. While the defects in the mouse model are more severe than those of the human patients, shared features include rib cage anomalies (Figure 2), digit anomalies (Figure 4), disruption of eye development (fully penetrant, described in text only), and severe morphological anomalies of the primary cilia in the limb buds (Figure 1G). While the model was generated using a mutagen, it is important to note that the targeted homozygous null mutant in Ift140 recapitulates the features of the model, albeit with enhanced severity. This confirms that the model's mechanism of pathogenicity is incomplete loss of Ift140 function. The localization of Ift140 protein to the base and tip of primary cilia in the limb bud is also consistent with the known function in humans (Figure 5F).

ModelVariant: The model does not feature any of the variants observed in human patients. Instead, the mutation is a missense change, c.2564T>A (p.Ile855Lys) in Ift140. The corresponding residue in human IFT140 is Thr854.

ExperimentName: IFT140 variant rescue in Ift140 knockout cells

RescueCellLine: Mouse Inner Medullary Collecting Duct 3 (mIMCD3) cells

RescueCellEFO: EFO:0002887 (mouse cell line), EFO:0001643 (kidney-derived cell line)

GeneAlteration: The cell line was subjected to CRISPR-based knockout of endogenous IFT140 (targeting exon 8).

RescueCellPhenotype: Ift140 knockout cells exhibited a complete inability to form cilia relative to the control rescued by overexpression of wild-type Ift140 (Figure 3b) and aberrant accumulation of the IFT-B protein IFT88 at the ciliary tip (Figure 3d).

RescueMethod: Transient transfection and over-expression of wild-type or variant IFT140 was used to rescue the cell phenotypes.

RescueEvidence: Wild-type IFT140 restored ciliogenesis in 11% of cells, while either variant restored ciliogenesis to 6%, despite the surprising continued absence of the frameshift variant at the protein level (Figure 3b). Wild-type IFT140 reduced the proportion of cells exhibiting IFT88 accumulation at the ciliary tip to 23%, while either variant partially reduced IFT88 localization to the ciliary tip to 50% or 56% (Figure 3d).

RescueCellVariant: The variants used for the rescue experiment were NM_014714.3(IFT140):c.992_993dup (p.Tyr332Valfs*18) (cannot be registered manually) and NM_014714.3:c.2767T>G (p.Tyr923Asp) (CA394227092).

ExperimentName: Mouse ciliated cell model of Ift140 loss-of-function

CellLine: Mouse Inner Medullary Collecting Duct 3 (mIMCD3) cells

CellEFO: EFO:0002887 (mouse cell line), EFO:0001643 (kidney-derived cell line)

GeneAlteration: The cell line was subjected to CRISPR-based knockout of endogenous IFT140.

CellPhenotype: Ift140 knockout cells exhibited a complete inability to form cilia relative to the control rescued by overexpression of wild-type Ift140 (Figure 3b).

CellEvidence: The defect in ciliary formation induced by Ift140 knockout (Figure 3b) recapitulates one of the cellular features of human patients harboring IFT140 variants (absence of cilia from a high proportion of fibroblasts). This also matches the Chlamydomonas model of IFT140 loss described in PMID: 28207750, albeit with greater severity.

CellVariant: CRISPR-based knockout was performed in this study to mimic IFT140 loss of function, while the human IFT140 variants were tested in the related rescue experiment instead.

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.

PMID: 22282595

Gene: IFT140

HGNC: 29077

Disease: polycystic kidney disease

MONDO: 0020642

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of polycystic kidney disease is between 1 in 400 and 1 in 1,000 individuals (PMID: 30523303).

Penetrance: Disease caused by monoallelic IFT140 variants is incompletely penetrant.

ExperimentName: Chlamydomonas mutant model of IFT140 loss-of-function

NonHumanModel: Chlamydomonas reinhardtii

GeneAlteration: The Ift140 mutant model has disruption of the Chlamydomonas gene by insertion of the paromomycin resistance gene AphVIII between bases 8234 and 8235 of the IFT140 gene (in exon 21 of 28).

ModelPhenotype: The mutant exhibits short flagella due to slower flagellar regeneration as well as absence of IFT43 and IFT122 (IFT-A proteins) from the peri-basal body (shown by immunofluorescent co-localization with α-tubulin).

HumanPhenotype: The human patients exhibit the absence of cilia from fibroblasts

ModelEvidence: The cellular defects of the model in flagellar regeneration/assembly (Figures 6A,6C) parallel the absence of cilia from a high proportion of patient fibroblasts. The model also helps explain this defect by showing the underlying cause; the absence of IFT-A complex components from the peri-basal body region (Figure 5E-5F).

ModelVariant: The model does not feature any of the variants observed in human patients.

PMID: 28207750

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.

PMID: 26216056

Gene: IFT140

HGNC: 29077

Disease: polycystic kidney disease

MONDO: 0020642

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of polycystic kidney disease is between 1 in 400 and 1 in 1,000 individuals (PMID: 30523303).

Penetrance: Disease caused by monoallelic IFT140 variants is incompletely penetrant.

SRF1186

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#: 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

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.

Selection B- Gene function is consistent with phenotype.

GOterm: GO:0030991 (intraciliary transport particle A)

FunctionalEvidence: Mass spectrometry analysis of IFT-A complex components co-purifying with the TULP3 protein identified the IFT140 protein along with several other known components such as WDR19, IFT122, THM1, and WDR35 (Figure 1C). These other IFT-A components were also confirmed by mass spectrometry to co-purify with IFT140 itself (Figure 1C).

FunctionalHPO: Absence of primary cilia in a high number of cells from the affected patients (shown using acetylated alpha-tubulin staining of cultured fibroblasts)

PhenotypeEvidence: Primary cilia from the affected patients are known to be absent from a high proportion of cells in the affected individuals, while the gene product functions in a complex known to participate in retrograde ciliary transport (Figure 1A, 1C). This trafficking process is known to be mediated by the IFT-A complex and is critical to the assembly and maintenance of 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.