MO022: Digenic inheritance in Alport syndrome

Abstract BACKGROUND AND AIMS The approach to Alport syndrome is a difficult task due to the phenotypic variability of its symptomatology, incomplete penetrance and its different forms of inheritance [1]. It presents a high degree of underdiagnosis, both because of erratic diagnosis as well as the existence of undiagnosed patients [2]. This study shows a patient carrying two pathogenic variants in COL4A3 and COL4A4 genes, respectively. The interest of the case lies in the low reported frequency of this type of inheritance, of which there are still no prevalence studies, but which may help to better understand this entity, as well as aid future diagnoses [3, 4]. METHOD Our index case is a 55-year-old male (IV.1). His medical history dates back to childhood when the disease began with microhematuria, repeated urinary tract infections, proteinuria and a progressive decrease in glomerular filtration rate until he required hemodialysis at 23 years. He received a living-renal transplantation from his mother, restarting hemodialysis at 49 years; a second engraftment was carried out 3 years later that was working for 5 years until a clear cell renal cancer was diagnosed and transplantectomy was required. There was no evidence of hearing or ocular impairment. Throughout the patient's follow-up, the existence of other relatives on the paternal side with kidney disease became known, and with the suspicion of hereditary origin, a genogram of the family was constructed with five generations [Figure 1]. A genetic study was performed using a next-generation sequencing (NGS) panel (Sophia Genetics) covering the coding and splicing regions of 44 genes related to HRE (Table 1). Subsequently, the study was extended to other relatives. RESULTS Molecular analysis identified two probably pathogenic variants in our index case and other relative at the moment, both in heterozygosis, one in exon 48 of the COL4A3 gene: c.4421T > C, p.(Leu1474Pro). This is a missense-type change in which thymine is replaced by cytosine at position 4421 of the coding sequence and predicts the substitution of the amino acid leucine by proline at position 1474 of the protein, affecting two functional domains. This variant is described and reported in the databases as pathogenic. On the other hand, it presents a deletion, also in heterozygosis, of exon 9 of the COL4A4 gene. Both variants were confirmed by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA), respectively. In this family, the variants co-segregate with the disease, although the analysis of other cases would be useful; furthermore, both variants co-segregate together, which indicates that the variants are in cis and both come from the same branch and neither has a de novo origin. CONCLUSION We have identified a case of digenic inheritance, two pathogenic variants in COL4A3 and COL4A4 genes respectively, thanks to the NGS techniques, of which very few cases have been described in the literature. Genetic analysis is the only way to confirm the diagnosis, often even to establish it after uncertain diagnoses; it is also the way to determine the mode of transmission and can often avoid the use of other invasive and not risk-free techniques such as skin or kidney biopsy. Although there is currently no curative treatment, early diagnosis is important to slow its progression, so that after the identification of a pathogenic variant, the family implications should be of special interest, to carry out adequate genetic counseling where family members at risk are informed and genetic study is offered, as well as the existing reproductive options for affected patients, such as preimplantation genetic testing or gamete donation. Otherwise, the offspring should be included in a program for early detection and monitoring of the disease.