Versions Compared

Version Old Version 1 New Version Current
Changes made by

Andrea Oza

Andrea Oza

Saved on

Key

  • This line was added.
  • This line was removed.
  • Formatting was changed.

...

Disease

Syndromic intellectual disability

Inheritance

Autosomal dominant

Prevalence

Expand
titlePossible sources

Orphanet

Medline Plus Genetics

 

Rapid or full curation?

  •  Rapid
  •  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - definitive https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_457f4be2-fe32-4878-b367-7fa614f78c63-2023-05-03T160000.000Z?page=1&size=25&search=

Clinical Validity Scoring Notes and points

The HNRNPR gene encodes a member of the spliceosome C complex, which functions in pre-mRNA processing and transport. Although the first HNRNPR variant was observed in a large epilepsy cohort in 2016 (PMID: 26795593), HNRNPR was first reported in relation to syndromic intellectual disability in 2019 by Duijkers et al. (PMID: 31079900). Overlapping clinical characteristics in 5 reported individuals included developmental delay/intellectual disability, microcephaly, seizures, facial dysmorphism, brachydactyly, and other congenital abnormalities. At least 6 variants have been reported in 9 probands, including 1 splice-site, 3 frameshift, 1 nonsense, and 1 missense variants (PMIDs: 26795593, 31079900, 33874999). Variants were de novo in all instances in which parental DNA was available. A frameshift and a missense variant were recurrent, identified in two and three unrelated probands, respectively. Other reported missense variants without functional characterization were of unclear pathogenicity and were not scored (PMID: 33874999).

Other members of the heterogeneous nuclear ribonucleoprotein (HNRNP) gene family have been recently implicated in neurodevelopmental disorders (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) (PMID: 33874999), supporting this gene-disease relationship.

In summary, there is definitive evidence supporting the relationship between HNRNPR and syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 3, 2023 (SOP Version 9).

Gene Clinical Validity Standard Operating Procedures (SOP) - SOP9

NOTE: All scored variants are NMD- (in last exon), curation for mol mech is below.

Clinical Validity Points Total

Clinical Validity Classification

Expand
titleClassifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Definitive

Molecular Mechanism

Expand
titleMechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function

PMID: 32319732

  1. c.619C>T p.(GIn207*) reported de novo in patient 1.

  2. c.395_401del p.(Asn132Thrfs*63) reported de novo in patient 4

  3. c.67C>T p.(Arg23*) de novo in patient 7

Gene is highly LOF constrained. LOEUF of 0.13. Unknown (but proposed Dominant Negative or GOF)

  • Gene is highly LOF constrained. LOEUF of 0.13.

  • Proposed dominant negative or GOF effect (PMID: 31079900).

    • The frameshift and nonsense variants identified in patients are expected to escape nonsense-mediated decay.

      • c.1609dupG (p.Ala537Glyfs∗10)

      • .1652dupG (p.Pro552Serfs∗34)

      • c.1663C>T, (p.Gln555Ter)

    • RNA sequencing of patient fibroblasts showed significant changes in the expression of other homeobox genes and transcription factors (Fig 4).

  • Only other variant in HGMD not already curated by ClinGen GCEP is c.498+1G>T (this would result in an in-frame deletion, see PMID: 33874999 for the reported case.

  • No NMD+ variants found via literature search, review of HGMD, consistent w/ variants in ClinVar image-20240903-191631.pngImage Added

Penetrance

Expand
titleoptions

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

Expand
titleoptions

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

Expand
titleOptions

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

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

Expand
titleExamples

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 09.03.24 SDSM-TA SF0467412 SP0467412 SDPT-RT 2021-230-261 3574359086

...