Renal Genetic Conditions

Autosomal Dominant Polycystic Kidney Disease - Gene

- PKD1 or PKD2

- Other rare genes

- LOF via truncating variants

- hypomorphic/non-truncating are less severe

- PKD1 contiguous gene deletion with TSC2

Autosomal Dominant Polycystic Kidney Disease - Symptoms

- primary ciliopathy

- liver cysts

- inguinal hernias

- cardiac valvular disease

- progressive renal disease -> HTN to acute to chronic pain to end stage renal disease

- Onset in 30s

- cysts throughout body, aneurysms of the brain, dilation of aortic root or thoracic aorta

- End stage renal disease in 60s

- mitral valve prolapse

Autosomal Dominant Polycystic Kidney Disease - Dx & Tx

- heterozygous P/LP in genes

- kidney imaging criteria and affected FDR

- monitoring kidney function

- head CTA or MRA

- manage cysts and pain levels

Autosomal Dominant Polycystic Kidney Disease - Gene Considerations

PKD1

- 50% hypomorphic -> have milder kidney disease

- non-truncating -> later age for end stage kidney disease onset

PKD2

- truncating -> more severe

Both

- biallelic PV (non-hypomorphic) -> lethal

- pseudogenes on chr. 16 (consider with testing)

Autosomal Recessive Polycystic Kidney Disease - Gene

- PKHD1

- Other rare genes: DZIP1L, CYS1

- AR inheritance

- Complete LOF variants

Founder variants in AJ & Afrikaner populations

May appear to have pseudodominance on pedigree due to higher carrier frequency in some populations

Autosomal Recessive Polycystic Kidney Disease - Symptoms

- Onset birth or shortly after (can be seen in utero)

- congenital hepatic fibrosis

- hepatobiliary disease

- splenomegaly

- enlarged kidneys, chronic kidney disease and failure

- hepatomegaly -> longer you live, more liver involvement

- death sometimes after birth but can live to 20s

Autosomal Recessive Polycystic Kidney Disease - Prenatal Findings

- oligohydramnios that can lead to Potter sequence

- bilateral nephromegaly

Autosomal Recessive Polycystic Kidney Disease - Dx & Tx

- biallelic P/LP in PKHD1

- perinatal/infantile: pulmonary disease, nephrectomy, dialysis, kidney transplant, feeding support

- childhood/young adulthood: above management + kidney &/or liver transplant, peritoneal dysplasia

Alport Syndrome - Genes

- AD/AR inheritance: COL4A3, COL4A4

- XL inheritance: COL4A5 (associated w/progressive SNHL)

- exhibits reduced penetrance

Alport Syndrome - Mechanism

- absence or reduced production of collagen IV in basement membranes of glomerulus, cochlea, & eye

- basement membrane supports endothelial & epithelial cells

Alport Syndrome - Symptoms

XL Alport (males) & AR Alport

- progressive kidney disease

- microhematuria leads to proteinuria leads to progressive kidney insufficiency leads to end stage renal disease

XL Alport (females) & AD Alport

- end stage kidney disease in later adulthood

- hearing loss later in life

- ocular findings are rare

Overall

- hematuria & proteinuria is variable

- SNHL -> late childhood (never congenital) & progressive

- retinal macular spots, LENTICONUS

Alport Syndrome - Diagnosis & Treatment

- genetic testing

- monitor kidney function & HTN

- consider kidney transplant as needed

- ophthalmology, audiology (hearing aids)

- diffuse leiomyomatosis (may need surgery)