Disease | |
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Inheritance | Autosomal recessive |
Prevalence | Source: |
Rapid or full curation? | |
ClinGen / GenCC / BabySeq / HGMD / OMIM | Cranioectodermal dysplasia - DOSAGE HI score of 30. No evidence provided. BabySEq - limited for Cranioectodermal dysplasia. GenCC - strong (Invitae) for short-rib thoracic dysplasia 18 with polydactyly and limited for retinitis pigmentosa. HGMD scoring below. |
Clinical Validity Scoring Notes and points | Sensenbrenner syndrome clinically overlaps with Jeune syndrome (also known as Asphyxiating Thoracic Dystrophy; ATD; MIM 208500). Skeletal anomalies such as brachydactyly, short limbs and a narrow thorax have been reported in both disorders. (PMID: 21378380) c.2T>A p.M1? - 0.00002978 4/44878 East Asian chromosomes. SHORT RIB POLYDACTYLY - SEVERE PHENOTYPE Duran 2017 28400947 - exome analysis. reduced expression in fibroblast compared to WT (Fig 1). Individuals R06-303A and E were homozygous for the variant. The phenotype was severe, fig 1 shows R06-303A, a 30-week gestational age fetus with dolichocephaly and a prominent occiput, a long narrow thorax with deformed ribs, micromelia, and poor mineralization of the distal limbs, mild platyspondyly, and abnormal ilia. Parents tested via Sanger and were carriers. 1 point x2 = 2 VARIANT POINTS Of note IFT43 is part of the IFT-A complex which includes IFT144 aka WDR19, definitive for ciliopathy, and the Kidney cystic and ciliopathy disorder GCEP lumped Cranioectodermal dysplasia 4 (OMIM:614378), Nephronophthisis 13 (OMIM:614377), Senior-Loken syndrome 8 (OMIM:616307), and Short-rib thoracic dysplasia 5 with or without polydactyly (OMIM:614376). Cites studies PMID: 22170070 and 24961486. PROTEIN INTERACTION 1 POINT
c.1A>G p.M1? - 1 ALLELE GNOMAD V4 Arts 2011 PMID: 21378380 snp array and sequencing used to find the variants in two siblings with Sensenbrenner syndrome from a consanguineous Moroccan family. Per description fig 1 phenotype includes (B) Absence of typical craniofacial features. (C) Rhizomelic shortening of limbs, narrow thorax. (D) Hypoplastic, cone shaped, and widely spaced teeth. (E) Bilaterial 2-3-4 toe syndactyly. (F) Brachydactyly, webbing of fingers, short and broad nails. (G) Frontal bossing, telecanthus, micrognathia, sparse and fine hair. (H) Rhizomelic shortening of limbs, narrow thorax. Haemodialysis catheter, Ciminoshunt left arm, gastrostomy. (I) Hypoplastic and widely spaced teeth. (J) Bilateral postaxial polydactyly, bilateral 2-3 toe and 5-6 toe syndactyly, sandal gap between 1-2 toes. (K) Brachydactyly, webbing of fingers, short and broad nails after surgical correction of postaxial polydactyly. Western blots revealed that the mutation disturbs translation of IFT43, inducing the initiation of translation of a shorter protein product from a downstream ATG. Scoring as an NMD- variant + functional, and as it is homozygous 2x1.5=3 POINTS VARIANT EVIDENCE Stained fibroblasts in one of the affected siblings and observed an accumulation of IFT-B complex proteins in the distal part of the ciliary axoneme and in the ciliary tip. EXPERIMENTAL PATIENT CELLS - 0.5 POINT Recently, it was shown that IFT43 directly binds to IFT121/WDR35, which supports a tight relationship between these two proteins.[PMID: 19450523] This is remarkable, since IFT121/WDR35 is the protein product of WDR35, a previously identified Sensenbrenner gene.[PMID: 20817137] -
JIA 2018 PMID: 29896747 - article in Chinese but abstract describes a girl with with Sensenbrenner syndrome, aka cranioectodermal dysplasia anemia and renal dysfunction homzygous for the variant, parents both het carriers. She had short stature, short limbs, brachydactylia, tooth agenesis, and retinal dystrophy, high-degree myopia, and chronic renal failure. 1 point x 2 = 2 POINT VARIANT EVIDENCE
c.73C>T p.R25* c.310+2T>C - did not curate c.535T>C p.W179R - absent gnomAD Duran 2017 28400947 - exome analysis. Found in proband with severe phenotype, Homozygous in R03-121A with 18-week gestational age fetus with short, narrow bent ribs, a bell-shaped chest, handlebar clavicles, curved humeri with short bent radii and ulnae, curved femurs, fibular aplasia and lack of calcification of the distal extremities. Significantly reduced levels observed in patient fibroblasts (fig 3). 0.5+0.5 point = 1 VARIANT POINT
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Clinical Validity Points Total | GENETIC EVIDENCE - 8 points EXPERIMENTAL - 1.5 |
Clinical Validity Classification Classifications (pts) Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed | MODERATE |
Molecular Mechanism Mechanisms Loss of function Gain of function Dominant negative Unknown Other | Unknown |
Penetrance options Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (list source/PMID) | Source: |
Age of Onset options Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID) | |
Severity Options Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers. | |
Clinical Features | From GeneREviews for Cranioectodermal dysplasia: Cranioectodermal dysplasia (CED) is a ciliopathy with skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly, polydactyly, brachydactyly), ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth deficiency, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage kidney disease in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur. PMID: |
HPO Terms https://hpo.jax.org/app/ | |
Gene SOPs & Notes | LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant |
Curation Summary Examples - The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited | |
Case ID, Curator name, Date, Jira ticket link | The IFT43 gene is associated with a spectrum of ciliopathies that include cranioectodermal dysplasia and short-rib thoracic dysplasia with polydactyly. The clinical features include nrrow thorax with deformed ribs, rhizomelic shortening of limbs, abnormal teeth (hypoplastic, cone shaped, widely-spaced), toe syndactyly, brachydactyly, abnormal nails, facial features such as frontal bossing, telecanthus, micrognathia, sparse and fine hair, postaxial polydactyly, renal involvement (PMID: 29896747, 28400947, 21378380, 24027799). Severity is variable. |