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| Fetal anomalies v8.19 | SLIT3 | Luke Stuart Classified gene: SLIT3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.19 | SLIT3 | Luke Stuart Gene: slit3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.18 | SLIT3 |
Luke Stuart gene: SLIT3 was added gene: SLIT3 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SLIT3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLIT3 were set to 29100090; 33933663; 12702769; 14550534; 32644051; 25691540; 37830982; 31613678 Phenotypes for gene: SLIT3 were set to congenital anomalies of kidney and urinary tract 1 (MONDO:0019719); congenital heart disease (MONDO:0005453); congenital diaphragmatic hernia (MONDO:0005711) Penetrance for gene: SLIT3 were set to unknown Review for gene: SLIT3 was set to AMBER Added comment: Evidence in humans autosomal recessive SLIT3-related congenital anomalies, including CAKUT and isolated congenital diaphragmatic hernia, are limited to a single published individual/ family. Animal knockout models are reported to show a variety of phenotypes with varying penetrance, including CAKUT-like features, congenital heart defects, and congenital diaphragmatic herina (CDH). Sanna-Cherchi et al., 2017; PMID: 29100090. Whole-exome sequencing identified homozygous NM_003062.3:c.1193delC, p.(Thr398SerfsTer37) in one individual with renal hypodysplasia/complex CAKUT and a congenital heart defect. The unaffected parents were heterozygous. Kaya et al., 2021; PMID: 33933663: A homozygous missense variant c.1528C>T (p.Arg510Cys) was reported in dizygous twins from one family with isolated CDH. Animal models: Homozygous Slit3−/− mice show congenital diaphragmatic hernia (CDH), associated with abnormal development/organisation of the central tendon of the diaphragm (PMID: 12702769; PMID: 14550534). Renal abnormalities, including kidney or ureter agenesis and renal hypoplasia, were reported in 20% of homozygotes surviving to adulthood and 40% of those dying neonatally (PMID 14550534). Other studies reported additional isolated phenotypes in homozygous Slit3−/− mice including osteopenia (PMID 32644051) and membranous ventricular septal defects (PMID: 25691540), and indeed SLIT3 has been associated with predisposition to congenital heart defects in humans (PMID 31613678). Right-ventricular enlargement was also reported in SLIT3-/- mice (PMID: 14550534) and was suspected to be secondary to CDH-induced pulmonary hypertension. Knockout mouse model phenotypes are reviewed in PMID 37830982. An additional NHS GMS family is described with a syndromic presentation including renal dysgenesis and renal insufficiency and a homozygous canonical splice (predicted frameshift) variant, segregating with disease in 3 affected family members (internal communications). No cardiac features nor CDH are cited. There is a lack of consistent phenotypic features reported in human subjects and animal models, with unclear penetrance. Thus an amber rating is recommended for CAKUT and congenital anomalies. SLIT3 is not associated with any disease or phenotype in OMIM, ClinGen. G2P cites a 'limited' association with SLIT3-related congenital anomalies. Sources: Literature |
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