Page 78 - GPD-4-2

Gene & Protein in Disease Alport syndrome: Genetics, variability, and management

more than 1% of many populations, making these genetic in cis, such as a combination of COL4A5 with COL4A3 or
alterations remarkably common. These variants often COL4A4, mirror autosomal dominant inheritance with
manifest within family histories, with a 50% likelihood of a recurrence risk of 50%. However, when mutations in
inheritance from an affected parent. 2 COL4A5 and COL4A3/4 coexist, the pattern of inheritance
The influence of gender on clinical outcomes in would not fit the typical Mendelian expectations, and a
ADAS remains ambiguous. Some studies indicate similar detailed family-specific risk assessment is necessary for
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prognoses between males and females, while others suggest these cases.
that males may experience a 5-year earlier decline in kidney 3.4.1. COL4A5 and COL4A3/COL4A4 in men
function compared to females. Kidney involvement is
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observed in approximately 92% of patients with ADAS, In males with COL4A5 mutations, additional COL4A3 or
with the median age of progression to ESKD of 67 years. 24 COL4A4 variants would not add to the clinical impact, as
all heterotrimers are already abnormal. At present, there is
Hearing loss and ocular involvement appear to be no evidence linking hypomorphic COL4A5 variants with
uncommon in these patients. When present, they tend worse outcomes. 25
to occur at older ages, and it seems that ophthalmologic
manifestations are even rarer than hearing loss. 23,24 3.4.2. COL4A5 and COL4A3/COL4A4 in women
However, these findings should be interpreted with Women with digenic AS have a higher likelihood of
caution since, due to the high prevalence of COL4A3 inheriting the disease due to the two X chromosomes
and COL4A4 mutations, medical attention may have they each carry. In cases of a COL4A5 mutation, about
predominantly focused on individuals with more severe half of the heterotrimers are affected, increasing to
disease phenotypes. This selection bias may result in an 75% if combined with a COL4A3 or COL4A4 variant.
overestimation of the true severity and progression of
ADAS in the broader population. However, the inheritance dynamics differ: For COL4A5
variants, X-chromosome inactivation leads to the loss of
There is evidence suggesting that a significant collagen IV α3α4α5-heterotrimers in about half of the
percentage of carriers of COL4A3 or COL4A4 variants cells, while for COL4A3 or COL4A4 variants, only half
exhibit minimal to no kidney disease. One study reported of the total heterotrimers in each cell are defective. 25,27
that, among individuals undergoing genetic testing, fewer The severity of the variant also matters. Severe COL4A5
than 3% progressed ESKD by the age of 60. Despite the mutations typically result in earlier loss of heterotrimers,
4
absence of clearly defined risk factors, carriers are at a whereas mild mutations impact only a subset of cells or
slightly increased risk for renal complications compared heterotrimers. These molecular mechanisms are consistent
to the general population. However, these variants should with clinical observations that the type of mutation
not be viewed as the sole explanation for kidney disease in significantly influences kidney disease prognosis. As
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affected individuals. Alternative or additional diagnoses, previously discussed, truncating mutations, such as
such as IgA nephropathy, should be considered when nonsense mutations or those resulting in stop codons,
evaluating such cases. 6 are associated with earlier-onset kidney failure compared
3.4. Digenic inheritance to missense mutations or splice-site variants. Therefore,
clinical presentation can range widely.
The widespread use of genetic testing has revealed several
cases of digenic AS caused by coexisting pathogenic 3.4.3. Heterozygous variants in COL4A3 and COL4A4
variants in COL4A5 and COL4A3 or COL4A4 or variants Studies show that pathogenic variants in both COL4A3 and
in both COL4A3 and COL4A4. These scenarios differ in COL4A4 seem to be prevalent, occurring up to 5 times as
population frequency, inheritance patterns, and clinical often as the different supracited digenic disease mutations.
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implications. Due to the low number of reported cases and These two pathogenic variants may occur in cis (same
limited follow-up, our current knowledge of the severity, chromosome) or in trans (opposite chromosome), resulting
progression, and inheritance of digenic AS remains in distinct inheritance patterns and varying probabilities
preliminary, reflecting only observed clinical tendencies. 25 of disease occurrence across successive generations.
This form of inheritance is non-Mendelian and While a single pathogenic variant in COL4A3 or COL4A4
can resemble both autosomal recessive and autosomal leads to 50% of collagen IV α3α4α5 heterotrimers being
dominant patterns under different conditions. In certain defective, the presence of two pathogenic variants in these
scenarios, mutations in trans (such as those in COL4A3 or genes increases the proportion of defective heterotrimers
COL4A4) can present with a 25% recurrence risk, aligning to 75% in both male and female populations. Studies
with autosomal recessive inheritance. However, mutations have shown that individuals with digenic pathogenic

Volume 4 Issue 2 (2025) 4 doi: 10.36922/gpd.7656