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What genetic defects lead to sporadic and familial Focal Segmental Glomerulosclerosis?
Over the past decade, much of the biology of the glomerular filtration barrier has been explained and defects in multiple structural and functional components of this barrier have been implicated in FSGS.
There are more than 50 genetic mutations associated with FSGS. Mutations may occur in podocyte structural components from genes such as NPHS2 (podocin), NPHS1 (nephrin), ACTN4 (alpha-actinin 4), TRPC6, alpha-5, beta-4 integrins, CD2AP may present as kidney-limited structural anomalies. Mutations in WT1, LAMB2, COQ2, and LMX1B have been identified as causative of syndromic conditions in which FSGS in only one of the multiple anomaly manifestations within an individual. Autosomal dominant inheritance patterns are documented in familial FSGS with ACTN4, TRPC6, and INF2, which were first implicated in adult-onset disease. Familial FSGS of childhood with NPHS1, NPHS2, and PLCE1 mutations are transmitted in an autosomal recessive pattern. Autosomal recessive and dominant inheritance patterns have been documented with child- and adult-onset FSGS.
List of Genes Implicated in Familial Focal Segmental Glomerulosclerosis
| GENE | PHENOTYPE |
|---|---|
| Autosomal Recessive | |
| NPHS1 (Nephrin) | FSGS; Congenital Nephrotic Syndrome |
| NPHS2 (Podocin) | FSGS; Congenital Nephrotic Syndrome |
| NPHS3 (PLCE1) | FSGS; Diffuse Mesangial Sclerosis |
| LAMB2 | FSGS; Pierson Syndrome |
| MYH9 | FSGS; Sensorineural Deafness; Macrothrombocytopenia; Epstein, Fechtner & Sebastian Syndromes |
| MYOE1 | FSGS |
| ADCK4 | FSGS |
| SGPL1 | FSGS; Adrenal Insufficiency; Ichthyosis; Acanthosis; Immunodeficiency |
| COQ6 | FSGS; Diffuse Mesangial Sclerosis; Sensorineural Deafness; Neurologic abnormalities |
| WDR73 | FSGS; Galloway-Mowat Syndrome |
| NUP93 | FSGS |
| NUP205 | FSGS |
| Autosomal Dominant | |
| ACTN4 | FSGS |
| ANLN | FSGS |
| ARHGAP24 | FSGS |
| CD2AP | FSGS |
| TRPC6 | FSGS |
| INF2 | FSGS; Charcot-Marie-Tooth Disease |
| LMX1B | FSGS; Nail-Patella Syndrome |
| PAX2 | FSGS; Papillorenal Syndrome |
| WT1 | FSGS; Denys–Drash, WAGR & Frasier Syndrome |
FSGS , Focal segmental glomerulosclerosis.
The prevalence of specific gene mutations in patients with FSGS depends on the ancestry of the cohort being studied. For example, NPHS2 mutations are found in 26% of children from families of Eastern European and Middle Eastern descent with familial FSGS and 19% of sporadic cases in that population. These mutations are rare causes of FSGS in Asian, African-American, and European-American populations of the United States. Apolipoprotein L1 (APOL1) has alleles that increase the risk of FSGS. These risk alleles are found in African Americans of west African descent. APOL1 polymorphisms convey protection against Trypanosoma brucei .
Genotype/phenotype correlations are still being investigated and have not yet reached the point of guiding clinical care with a few notable exceptions:
• Genetic testing of patients with FSGS may be considered during the assessment of infantile FSGS
• FSGS that is part of a multiple congenital anomaly syndrome
• Familial FSGS, in regions with a high prevalence of consanguinity
• In some cases, prior to kidney transplantation to assess the risk of FSGS recurrence
