Diseasy Severity in patients with heterozygous COL4A3 or COL4A4 pathogenic Variants and Exploration of Risk factors.

Alport syndrome (AS) is a hereditary disorder of type IV collagen and is
characterized by the combination of kidney injury, hearing loss, and eye
abnormalities. Three genes encode the type IV collagen chains of the glomerular
basement membrane. The majority AS cases are caused by mutations in the COL4A5
gene on the X chromosome. Autosomal Alport syndrome is caused by pathogenic
variants in either COL4A3 or COL4A4 gene. Classically, patients with two
pathogenic variants (homozygous or compound heterozygous) developed Alport
syndrome, whereas patients with one variant (heterozygous) developed
(non-progressive) thin basement membrane nephropathy (TBMN). Recent advances in
genetic diagnostic testing have resulted in the identification of heterozygous
COL4A3/COL4A4 genetic variants in patients with chronic kidney disease (CKD)
who were not diagnosed with AS or TBMN. Remarkably, there is marked
heterogeneity between and within families with respect to the clinical course,
and very few patients have extrarenal signs/symptoms. This heterogeneity is a
serious limitation in patient care, and prohibits adequate counselling of
patients.
The aim of the project is to find explanations for intra- and inter-familial
heterogeneity among patients with established COL4A3/COL4A4 heterozygous
variants.
The central hypothesis of the project is that phenotypic heterogeneity in
patients with one heterozygous COL4A3/COL4A4 pathogenic variant is at least
partly explained by hitherto unrecognized second hits. The unrecognized second
hits may be environmental or genetic, either localized in the COL4A3 or COL4A4
genes (intronic variants or somatic variants in the kidney), or in other
podocyte-associated genes.

To accomplish this aim we will address the following objectives:
1. Define kidney disease heterogeneity within and between families carrying
heterozygous COL4A3/COL4A4 pathogenic variants and evaluate hearing loss as
non-renal phenotype;
2. Analyze environmental factors explaining variations in disease severity;
3. Depending on the outcome of obj. 2: Investigate the presence of intronic and
somatic COL4A3/COL4A4 pathogenic variants;
4. Depending on the outcome of obj. 2 and 3: Investigate the presence of rare
variants in other podocyte-associated genes.

Observational cross-sectional study.

Risks associated with participation are minimal. One clinic visit to the
outpatient clinic is required to collect blood and urine samples (and a hearing
test for index patients) and one additional urine sample will be sent by post.
No additional interventions are required. There is no direct benefit for the
patients.
The benefit for patients and families with heterozygous COL4A3/COL4A4
pathogenic variants is the potential insights in risk factors (lifestyle and
genetic factors) contributing to the development of kidney failure. This can
lead to optimal counselling strategies in the future.

Disclosure of individual results
Participants will be informed about the possible results and consequences of
genetic testing. Since we will only focus on COL4A-genes and
podocyte-associated genes and not perform open whole-exome sequencing chances
of other secondary findings are extremely limited. Results of genetic testing
will only be disclosed if individual results have a clinical impact for the
individual: likely pathogenic or pathogenic variants based on the joint
guideline of the Association of Clinical Genetic Laboratory Diagnostics (VKGL)
and Association for Clinical Genetic Science (ACGS).

A clinical genetic specialist will always be involved when informing a
participant about the results of genetic testing with implications for the
health of the participant or family.