Identification of disease-causing variants by comprehensive genetic testing with exome sequencing in adults with suspicion of hereditary FSGS

Abstract

In about 30% of infantile, juvenile, or adolescent patients with steroid-resistant nephrotic syndrome (SRNS), a monogenic cause can be identified. The histological finding in SRNS is often focal segmental glomerulosclerosis (FSGS). Genetic data on adult patients are scarce with low diagnostic yields. Exome sequencing (ES) was performed in patients with adult disease onset and a high likelihood for hereditary FSGS. A high likelihood was defined if at least one of the following criteria was present: absence of a secondary cause, ≤25 years of age at initial manifestation, kidney biopsy with suspicion of a hereditary cause, extrarenal manifestations, and/or positive familial history/reported consanguinity. Patients were excluded if age at disease onset was <18 years. In 7/24 index patients with adult disease onset, a disease-causing variant could be identified by ES leading to a diagnostic yield of 29%. Eight different variants were identified in six known genes associated with monogenic kidney diseases. Six of these variants had been described before as disease-causing. In patients with a diseasecausing variant, the median age at disease onset and end-stage renal disease was 26 and 38 years, respectively. The overall median time to a definite genetic diagnosis was 9 years. In 29% of patients with adult disease onset and suspected hereditary FSGS, a monogenic cause could be identified. The long delay up to the definite genetic diagnosis highlights the importance of obtaining an early genetic diagnosis to allow for personalized treatment options including weaning of immunosuppressive treatment, avoidance of repeated renal biopsy, and provision of accurate genetic counseling.

Monogenic focal segmental glomerulosclerosis: A conceptual framework for identification and management of a heterogeneous disease

“…In a French cohort of patients with sporadic SRNS or FSGS and lack of response to glucocorticoids and cyclosporin, 11% had pathogenic variants in monogenic SRNS genes while another 10% had two high‐risk APOL1 risk alleles (Gribouval et al, 2018). In another recent study from Europe of sporadic FSGS where other secondary causes had been excluded, comprehensive genetic testing yielded a genetic cause of non‐syndromic FSGS in 12% patients (Braunisch et al, 2021). The most common genes responsible for adult onset FSGS are the Alport genes, COL4A3 , COL4A4 and COL4A5 with rates of 38–55% in those with genetic FSGS (Gast et al, 2016; Yao et al, 2019) followed by INF2 (~17%), TRPC6 (~12%) and ACTN4 (3.5%) (Rood, Deegens, & Wetzels, 2012).…”

“…The most common genes responsible for adult onset FSGS are the Alport genes, COL4A3 , COL4A4 and COL4A5 with rates of 38–55% in those with genetic FSGS (Gast et al, 2016; Yao et al, 2019) followed by INF2 (~17%), TRPC6 (~12%) and ACTN4 (3.5%) (Rood, Deegens, & Wetzels, 2012). With the slow adoption of genetic testing in the evaluation and management of FSGS, there can be a long delay (~9 years) from the time of disease onset to establish a genetic diagnosis (Braunisch et al, 2021).…”

“…With the slow adoption of genetic testing in the evaluation and management of FSGS, there can be a long delay ($9 years) from the time of disease onset to establish a genetic diagnosis (Braunisch et al, 2021).…”

Which patients with CKD will benefit from genomic sequencing? Synthesizing progress to illuminate the future

“…Reaffirmation of proposed key factors indicating higher likelihood of an identifiable monogenic cause in CKD and thus a diagnostic outcome from genomic testing is clarifying clinical utility. Such factors include the presence of a family history of kidney disease [ 47 ], younger age of onset [ 48 ], extra-renal features, and phenotype-specific factors [ 49 ]. This is critical to frame clinical utility and to guide future implementation and education.…”

Ocular manifestations of the genetic causes of focal and segmental glomerulosclerosis

“…There are however clues to the likelihood of a genetic basis for FSGS [ 7 ]. These include a positive family history [ 8 ], a young age at onset [ 9 ], SRNS [ 10 ] and no other obvious cause [ 11 ]. The association with extra-renal features, such as a hearing loss, skeletal, cardiac or ocular anomalies, is also important [ 12 ].…”