CAKUT
Gene: CHD1LComment on list classification: Following expert review that some of the reported variants in this gene are relatively common in gnomAD and therefore unlikely to associated with a Mendelian disease, downgrading this gene from amber to red.Created: 1 Jul 2020, 4:13 p.m. | Last Modified: 1 Jul 2020, 4:13 p.m.
Panel Version: 1.153
Comment on list classification: Updated rating from Red to Amber. Although there are 8 families with CAKUT and CHD1L variants, all variants are missense, and there is limited family data available for the patients in PMID:22146311. Also in PMID:22146311, only 2/3 variants were absent from controls, Patient 2 variant was inherited from an asymptomatic mother, and the variant in Patient 3 is predicted benign.Created: 30 Apr 2020, 1:21 p.m. | Last Modified: 30 Apr 2020, 1:21 p.m.
Panel Version: 1.65
PMID:32164334 show CNVs in genes including CHD1L in 6 CAKUT patients. One patient with bilateral renal cortical cysts and renal stones (ID 41) had a duplication of 1q21.1 encompassing CHD1L.Created: 30 Apr 2020, 1:19 p.m. | Last Modified: 30 Apr 2020, 1:19 p.m.
Panel Version: 1.64
PMID:24429398 (2014) detected heterozygous variants in CHD1L in 5 families with CAKUT (p.P333R in 1 family, p.E400G in 1 family, p.I517M in 3 Indian families).Created: 30 Apr 2020, 1:07 p.m. | Last Modified: 30 Apr 2020, 1:10 p.m.
Panel Version: 1.63
PMID:22146311. Brockschmidt et al., 2012 screened 85 CAKUT patients for variants in CHD1L and found 3 patients. Patient 1 had a hypodysplastic right kidney with VUR and variant Gly700Arg, which was not found in controls. Parents not available for testing.
Patient 2 had bilateral massive hydronephrosis due to obstructive megaureters, and chromic renal failure. Ile765Met was inherited from the mother who had no kidney/urinary tract anomalies on ultrasound. Ile765Met was found in 1/430 controls.
Patient 3: had bilateral hypodysplasia of the kidneys. Variant Ile827Val was inherited from the father who wasn't available for analysis. Ile827Val is predicted to be benign.
Expression and functional studies show that CHD1L is localized to postnatal kidneys and interacts with PARP1.Created: 30 Apr 2020, 1:04 p.m. | Last Modified: 30 Apr 2020, 1:04 p.m.
Panel Version: 1.63
Re-evaluation in light of population data: the 6 missense variants reported in the two papers (PMID: 22146311, 24429398) are very common in gnomAD: CHD1L:c.2098G>A; p.Gly700Arg - 1110 hets, 5 hom CHD1L:c.2295A>G; p.Ile765Met - 468 hets, 1 hom CHD1L:c.2479A>G; p.Ile827Val – 725 hets, 2 hom CHD1L:c.998C>G; p.Pro333Arg – 1 het, 0 hom CHD1L:c.1199A>G; p.Glu400Gly – 3 hets, 0 hom CHD1L:c.1551A>G; p.Ile517Met – 195 hets, 0 hom I could not find any other papers for this gene in association with CAKUT. ClinVar only has 1 frameshift variant reported as pathogenic from research in 2001 for an unrelated condition (short stature), the other variants reported in this gene are VUS or LB/B. These population variant frequencies are out of keeping for a Mendelian disorder.Created: 18 Jun 2020, 10:42 a.m. | Last Modified: 18 Jun 2020, 10:42 a.m.
Panel Version: 1.152
Despite the assessment by ClinGen, there are 8 reported families.Created: 16 Jan 2020, 3:31 a.m. | Last Modified: 16 Jan 2020, 3:31 a.m.
Panel Version: 1.41
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
CAKUT
Publications
Comment on list classification: Rated red to reflect the limited evidence found by the ClinGen group.Created: 25 Jul 2017, 8:41 a.m.
ClinGen Gene Validity Classification Summary. Determined as LIMITED by calculated classification (dated: 05/25/2016) and LIMITED by Expert curation (dated 11/18/2016). Available here: https://search.clinicalgenome.org/kb/gene-validity/3220.Created: 25 Jul 2017, 8:41 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Renal or urinary tract malformation (CAKUT); ORPHA93545
Publications
Gene: chd1l has been classified as Red List (Low Evidence).
Tag missense tag was added to gene: CHD1L.
Gene: chd1l has been classified as Amber List (Moderate Evidence).
Publications for gene: CHD1L were set to 24429398; 22146311
This gene has been classified as Red List (Low Evidence).
CHD1L was added to CAKUTpanel. Sources: Other
CHD1L was created by ellenmcdonagh