Inheritance

X-linked

Prevalence

 1:300,000 males

Source: PMID: 20301508

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD

ClinGen - no curation; GenCC - Definitive by LMM, no other submitters; BabySeq - Definitive (PMIDs: 2062380, 25449081, 18560135, 24361063).

Clinical Validity Scoring Notes and points

n/a, using BabySeq (PMID: 28079900)) curation of Definitive

Source: PMIDs: 2062380, 25449081, 18560135, 24361063

Clinical Validity Points Total

Source:

Clinical Validity Classification

Definitive

Source: 28079900

Molecular Mechanism

UNKNOWN (Not LOF, since LOF variants cause androgen insensitivity)

Triplet repeat expansion - CAG in intron 1

• Normal: ≤ 35 or fewer

• Uncertain range: 36-39

• Pathogenic: ≥ 40

Lit. notes:

• GeneReviews PMID: 20301508 - Normal - 34 or fewer, mutable normal (ie premutation) - non reported to date; reduced penetrance - 36-37; Full penetrance - 38. No citations listed here. I cant find where the lower limit of 38 repeats comes from.

• gnomAD - thresholds are Normal ≤ 35, Pathogenic ≥ 40. Total of 4 alleles that are 40 repeats or greater.

• PMID:16621916 - 223 SBMA patients, mean number of repeats was 46.6 (range - 40-57)

• PMID: 9724012 - 13 Finnish individuals with features of Kennedy disease identified to have CAG repeat expansion. Affected individuals had repeats that were between 41-47 repeats in length. Unaffected individuals had repeats sized at 16-26.

• PMID: Normal range

• PMID: 11266016 - 37 repeats identified in two unaffected individuals, suggesting this could be part of the reduced penetrance range. Text cites several studies that max number of repeats is 35, and 38-62 have been found in SBMA patients. But the citations listed do not describe a repeat at 38

  • PMID: 8213813 - Unaffected individuals had up to 35 repeats.

  • PMID: 7998766 - review, pathogenic range listed 40-62 and normal 11-34

• PMID: 24041967 - Text suggests disease threshold is 38 repeats, along with table 1. But their cohort shows that affected individuals have between 40-54 repeats

Summary - Clear that 40 alleles is sufficient to cause disease. Multiple papers cite 38 repeats as pathogenic, but looking into the references they cite, I can’t find the evidence.

Penetrance

(list source/PMID)

Complete - 40 alleles or higher is expected to be full penetrance. Repeats in the uncertain range could be incomplete penetrance.

Source:

Age of Onset

(list source/PMID)

Adulthood

Source PMID: 20301508

Severity

Moderate

Clinical Features

Neuromuscular findings - falling tendency, muscle cramps, action tremor, decreased deep tendon reflexes, atrophy of proximal and distal muscles, bulbar muscle involvment (speech articulation and swallowing, aspiration pneumonia, ventilatory failure).

Cardiac - abnormal cardiac rhythms, HCM

Metabolic - hyperlipidemia, insulin resistance.

Electrodiagnostic - diffuse denervation atrophy, anterior horn cell loss, and sensory neuronopathy

Histopathology - Immunohistochemistry shows inclusions of mutated androgen receptor protein

Androgen insensitivity - gynecomastia

Heterozygous females may have muscle cramps or occasional tremors, but no significant motor neuron disease.

Sources: PMID: 20301508

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

Triplet repeat disorder, see molecular mechanism section

Curation Summary

The AR gene is associated with X-linked Spinal and bulbar muscular atrophy (aka Kennedy disease), which is characterized by neuromuscular findings, cardiac rhythm abnormalities, hyperlipemia, insulin resistence, and androgen insensitivity. It is caused by an expansion of the CAG repeat in exon 1. The AR gene is also associated with androgen insensitivity syndrome.

Case ID, Curator name, Date, Jira ticket link

https://broadinstitute.atlassian.net/browse/BCL-168 Andrea Oza, 09.08.2023

Inheritance

Autosomal recessive / autosomal dominant / X-linked

Prevalence

Source:

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD

Clinical Validity Scoring Notes and points

Variant/Case Evidence:

Segregation Evidence:

Case/Control Evidence:

Experimental Evidence:

Source:

Clinical Validity Points Total

Source:

Clinical Validity Classification

Source:

Molecular Mechanism

Loss of function / Gain of function / Dominant Negative

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Severity

Clinical Features

Sources:

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

Case ID, Curator name, Date, Jira ticket link