CHD1L – CHD1L-related Congenital Anomalies of the Kidney and Urinary Tract

CHD1L encodes a chromatin-remodeling enzyme with high expression in human fetal kidneys, implicating it in nephrogenesis. Variants in CHD1L have been recurrently observed in patients with congenital anomaly of kidney and urinary tract (CAKUT), supporting an autosomal dominant mechanism of dysregulated renal development. Early genetic screens and functional assays converge on CHD1L as a candidate CAKUT gene.

In a cohort of 650 families (749 probands) with isolated CAKUT, heterozygous CHD1L variants were identified in five unrelated families, representing 6.3% of solved cases and demonstrating recurrence across independent kindreds (PMID:24429398). No unaffected relatives carried these variants, consistent with dominant segregation.

Targeted exome sequencing of 94 Korean CAKUT patients revealed pathogenic copy number variants involving CHD1L in one patient, contributing to a 13.8% diagnostic yield across known CAKUT genes (PMID:32164334). This structural alteration further confirms the gene’s dosage sensitivity in renal morphogenesis.

Trio-based exome sequencing in 209 CAKUT families identified additional CHD1L allele carriers, including de novo events, in multiple trios (19.62%), reinforcing its role in sporadic CAKUT etiology (PMID:40223730). These findings extend case-level evidence and underscore de novo dominance.

Functional studies of three heterozygous CHD1L missense variants showed impaired PARP1 interaction in pull-down assays, elevated CHD1L expression in the ureteric bud and S-/comma-shaped bodies, and recapitulation of fetal expression patterns in hydronephrotic tissue. These results implicate a loss-of-function mechanism through haploinsufficiency of the PAR-binding macro domain (PMID:22146311).

No conflicting reports have been published to dispute CHD1L’s role in CAKUT. Integration of genetic and experimental data supports a coherent autosomal dominant model of CHD1L haploinsufficiency causing renal tract malformations. Key take-home: CHD1L should be included in diagnostic gene panels for children with congenital renal anomalies.

References

• Kidney International | 2014 | Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract. PMID:24429398
• Journal of clinical medicine | 2020 | Targeted Exome Sequencing Provided Comprehensive Genetic Diagnosis of Congenital Anomalies of the Kidney and Urinary Tract. PMID:32164334
• Genetics in medicine | 2025 | Trio exome sequencing identifies de novo variants in novel candidate genes in 19.62% of CAKUT families. PMID:40223730
• Nephrology, dialysis, transplantation | 2012 | CHD1L: a new candidate gene for congenital anomalies of the kidneys and urinary tract (CAKUT). PMID:22146311

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