Kidney Week 2025 Early Program - Genetics in Clinical Nephrology-Workshop 1 Onsite Handout

Workshop 1 Onsite Handout

Pdf Summary

A 37-year-old man with autism spectrum disorder and ADHD, limited education, and significant anxiety is evaluated in a genetics workshop scenario. He has no children. Family history is notable for a sister (42) with at least six miscarriages around 3–4 months’ gestation and one gout episode, a healthy brother with three healthy children, a mother (64) with hypertension and a maternal aunt with breast cancer, and limited information about a sudden maternal grandmother death at 45. Paternal history includes suspected long-standing diabetes in the father (64, estranged), a paternal aunt also on the autism spectrum whose teenage son has a solitary kidney, and a paternal grandmother who had gout and diabetes, required dialysis for several years, and died in her 60s.

Genetic testing performed was a “genetic panel for cystic kidney diseases.” The overall result is reported as <strong>negative</strong> (no diagnostic variant identified). However, the report lists several <strong>variants of uncertain significance (VUS)</strong> in autosomal dominant disease-associated genes: <strong>COL4A1</strong> (heterozygous VUS), <strong>SEC61A1</strong> c.299T>C (p.Ile100Thr), heterozygous VUS, and <strong>UMOD</strong> c.1570C>T (p.Gln524Ter), heterozygous VUS.

In addition, carrier status findings include heterozygous pathogenic variants in recessive nephronophthisis-related genes: <strong>GLIS2</strong> (in-frame deletion, pathogenic) and <strong>NPHP1</strong> (frameshift, pathogenic), plus a <strong>CEP290</strong> splice-site change listed without a classification in the excerpt. These heterozygous recessive variants typically indicate carrier status rather than a diagnosis unless a second pathogenic variant is present.

A key limitation is that the panel detects only SNVs and small indels; <strong>copy-number variants are not assessed</strong>, so some genetic causes could be missed.

Keywords

cystic kidney disease genetic panel

negative genetic test result

variants of uncertain significance (VUS)

COL4A1 heterozygous variant

SEC61A1 c.299T>C (p.Ile100Thr)

UMOD c.1570C>T (p.Gln524Ter)

nephronophthisis carrier status

NPHP1 frameshift pathogenic variant

GLIS2 in-frame deletion pathogenic variant

copy-number variants not assessed (CNV limitation)