A Master in Mimicry: Expanding the Renal Phenotype of COL4A1-Related Disorders
Laboratory Genetics and Genomics
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Primary Categories:
- Laboratory Genetics
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Secondary Categories:
- Laboratory Genetics
Introduction:
COL4A1-related disorders (COL4A1-RD), such as HANAC (Hereditary Angiopathy, Nephropathy, Aneurysms and Cramps), are autosomal dominant rare genetic disorders that affect multiple systems in the body such as the brain, eyes, heart, muscles and kidneys. Renal manifestations associated with HANAC, including kidney cysts, increased kidney volume, decreased function and microscopic hematuria, are primarily associated with variants in exons 24 and 25 of COL4A1. However, additional studies have identified “HANAC-like” patients with variants outside exon 24 or 25 who exhibit kidney findings. This suggests there is no specific genotype-phenotype relationship for COL4A1 kidney features and underscores our incomplete understanding of these disorders.
Here, we examined the diverse phenotypes associated with variants in COL4A1 in a kidney disease-focused population.
Methods:
Patients who underwent comprehensive genetic testing with the RenasightTM test and had a positive result for a (likely) pathogenic COL4A1 variant were identified. A questionnaire was sent to the patient’s provider to gather additional information regarding renal and extrarenal symptoms. A retrospective analysis of clinical information including ICD10 codes was performed to determine clinical diagnoses and to gain information on patients’ clinical features (i.e. reverse phenotyping). Data was de-identified and aggregated into summary categories.
Results:
Out of 66 patients with (likely) pathogenic variants in COL4A1, follow-up phenotypic information was provided for 28, who were included in this study. A total of 24 unique variants were identified, of which 87.5% (n=21) were located outside of exons 24 and 25 in the COL4A1 gene. The majority of the identified variants in this cohort (83.3%, 20/24) have not been previously reported in the literature. Four patients had a second positive finding in another gene: PKD1 (n=1), COL4A5 (n=1), and TRPC6 (n=2). The ICD10 codes reported among this cohort were CKD 1-5 (42.9%, 12/28), hematuria (28.6%, 8/28), cysts (17.9%, 5/28) and Alport syndrome (10.7%, 3/28). Most cases (68.0%, 19/28) had a priori clinical diagnoses of Alport syndrome (35.7%, 10/28) and ADPKD (32.1%, 9/28).
Questionnaire responses from the providers indicated variable renal features in these patients, including hematuria (42.9%, 12/28), proteinuria (17.9%, 5/28) and cysts (35.7%,10/28). Extrarenal features included neurological features (21.4%, 6/28), ocular findings (3.6%, 1/28), muscle cramps (7.1%, 2/28) and arrhythmia (7.1%, 2/28). The patients with additional positive findings in PKD1 and COL4A5 had a priori diagnosis of ADPKD and Alport syndrome, respectively. None of the 28 patients had an a priori diagnosis of HANAC disorder.
Among the respondent providers, 39.3% (11/28) indicated that COL4A1 results would change their patients’ management. The reported changes included (1) subspecialist referrals such as medical genetics, ophthalmology and neurology, (2) additional tests such as brain MRI/MRA and cardiac monitoring, and (3) changes to medication such as starting a new medication like an ACE inhibitor or RAAS blockade or discontinuing medication when the a priori diagnosis was inaccurate.
Conclusion:
To our knowledge, this is the first study to examine clinical symptoms in a kidney-first population with P/LP COL4A1 variants. Most variants reported in our cohort were outside COL4A1 exons 24 and 25, suggesting kidney features are not limited to these exons. The data also suggest that extrarenal screening may be warranted for those with a COL4A1-RD. Our results also support using a multigene panel for common kidney indications like hematuria and cysts, because it may identify a hereditary diagnosis that would have been missed with limited testing. An accurate molecular diagnosis provides patients with the potential of improved care and disease management. These findings add to the literature, as most identified variants were previously unreported and expand the genetic region previously associated with HANAC, highlighting the potential for new insights into the genetic basis of these disorders.
COL4A1-related disorders (COL4A1-RD), such as HANAC (Hereditary Angiopathy, Nephropathy, Aneurysms and Cramps), are autosomal dominant rare genetic disorders that affect multiple systems in the body such as the brain, eyes, heart, muscles and kidneys. Renal manifestations associated with HANAC, including kidney cysts, increased kidney volume, decreased function and microscopic hematuria, are primarily associated with variants in exons 24 and 25 of COL4A1. However, additional studies have identified “HANAC-like” patients with variants outside exon 24 or 25 who exhibit kidney findings. This suggests there is no specific genotype-phenotype relationship for COL4A1 kidney features and underscores our incomplete understanding of these disorders.
Here, we examined the diverse phenotypes associated with variants in COL4A1 in a kidney disease-focused population.
Methods:
Patients who underwent comprehensive genetic testing with the RenasightTM test and had a positive result for a (likely) pathogenic COL4A1 variant were identified. A questionnaire was sent to the patient’s provider to gather additional information regarding renal and extrarenal symptoms. A retrospective analysis of clinical information including ICD10 codes was performed to determine clinical diagnoses and to gain information on patients’ clinical features (i.e. reverse phenotyping). Data was de-identified and aggregated into summary categories.
Results:
Out of 66 patients with (likely) pathogenic variants in COL4A1, follow-up phenotypic information was provided for 28, who were included in this study. A total of 24 unique variants were identified, of which 87.5% (n=21) were located outside of exons 24 and 25 in the COL4A1 gene. The majority of the identified variants in this cohort (83.3%, 20/24) have not been previously reported in the literature. Four patients had a second positive finding in another gene: PKD1 (n=1), COL4A5 (n=1), and TRPC6 (n=2). The ICD10 codes reported among this cohort were CKD 1-5 (42.9%, 12/28), hematuria (28.6%, 8/28), cysts (17.9%, 5/28) and Alport syndrome (10.7%, 3/28). Most cases (68.0%, 19/28) had a priori clinical diagnoses of Alport syndrome (35.7%, 10/28) and ADPKD (32.1%, 9/28).
Questionnaire responses from the providers indicated variable renal features in these patients, including hematuria (42.9%, 12/28), proteinuria (17.9%, 5/28) and cysts (35.7%,10/28). Extrarenal features included neurological features (21.4%, 6/28), ocular findings (3.6%, 1/28), muscle cramps (7.1%, 2/28) and arrhythmia (7.1%, 2/28). The patients with additional positive findings in PKD1 and COL4A5 had a priori diagnosis of ADPKD and Alport syndrome, respectively. None of the 28 patients had an a priori diagnosis of HANAC disorder.
Among the respondent providers, 39.3% (11/28) indicated that COL4A1 results would change their patients’ management. The reported changes included (1) subspecialist referrals such as medical genetics, ophthalmology and neurology, (2) additional tests such as brain MRI/MRA and cardiac monitoring, and (3) changes to medication such as starting a new medication like an ACE inhibitor or RAAS blockade or discontinuing medication when the a priori diagnosis was inaccurate.
Conclusion:
To our knowledge, this is the first study to examine clinical symptoms in a kidney-first population with P/LP COL4A1 variants. Most variants reported in our cohort were outside COL4A1 exons 24 and 25, suggesting kidney features are not limited to these exons. The data also suggest that extrarenal screening may be warranted for those with a COL4A1-RD. Our results also support using a multigene panel for common kidney indications like hematuria and cysts, because it may identify a hereditary diagnosis that would have been missed with limited testing. An accurate molecular diagnosis provides patients with the potential of improved care and disease management. These findings add to the literature, as most identified variants were previously unreported and expand the genetic region previously associated with HANAC, highlighting the potential for new insights into the genetic basis of these disorders.