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MORC2 Gene Curation

MORC2 Gene Curation

Owned by Andrea Oza
Last updated: 2025-02-07
4 min read

Gene-disease assertions not curated here (add link or write note): Charcot-Marie Tooth - Definitive by ClinGen GCEP, their summary states it was split for curation from the AD neurodev syndrome)

Disease

MORC2-related neurodevelopmental syndrome

Disease

MORC2-related neurodevelopmental syndrome

Inheritance

Autosomal dominant

Prevalence

Orphanet

Medline Plus Genetics

 

Source:

Rapid or full curation?

Rapid
Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

AD Leigh syndrome curated as limited by mito GCEP in 2021. GenCC only has 1 curation (strong by Invitae). Curating variants from HGMD below

Clinical Validity Scoring Notes and points

PMID: 32693025 (2020)

  • NM_001303256.3:c.79G>A p.Glu27Lys (absent gnomAD)

    • Glu27Lys in table 1, de novo in patients 2, 3, 4, 6 and unknown inheritance in patient 5. Features include growth restriction, microcephaly, motor delay, speech delay, ID, hearing loss, hyper and hyporeflexia, abnormal brain MRI. Per the main text, they included parents in trio analysis when available, so I am going to assume parentage confirmed for the de novo individuals. 0.5 x 5 VARIANT POINTS + 0.4 X 4 DE NOVO = 4.5 VARIANT POINTS

  • NM_001303256.3:c.260C>T SER87LEU (absent gnomAD)

    • De novo in patients 7, 8. 2 x 1 POINT = 2 VARIANT POINTS

    • NOTE - These patients also have axonal motor neuropathy (consistent with CMT)

  • NM_001303256.3:c.394C>T Arg132Cys (absent gAD)

    • de novo in patients 10, 11, 12, not know in patients 13. (0.5 x 4) + (0.5 x 3 de novo) = 3.5 VARIANT POINTS

  • NM_001303256.3:c.1181A>G p.Tyr394Cys (absent gAD)

    • de novo in patients 17 and 18. 2 x 1 point = 2 VARIANT POINTS

  • FUNCTIONAL: MORC2-deficient cells harboring a HUSH-sensitive GFP reporter were transduced with lentiviral vectors encoding either wild-type MORC2 or variant, p.Thr24Ile, p.Glu27Lys, p.Ser87Leu, p.Arg132Cys, p.Arg266Ser, and p.Val413Phe variants hyperactivated HUSH-mediated silencing (fig 3B and c). BIOCHEMICAL FUNCTION 1 POINT

12 POINTS REACHED - additional scoring for replication over time

PMID: 36791574 (2023)

  • NM_001303256.3:c.79G>A p.Glu27Lys (absent gnomAD)

    • De novo in patient 1. Phenotype described in table 2 - gait abnormalities, abnormal brain MRI, hypotonia, limb wekaness, short stature, motor delay, ID, hearing loss, retinotpathy. Per the methods, it sounds like testing was done via Sanger, and parents tested later.

  • NM_001303256.3: c.260C>T p.(Ser87Leu) (absent gnomAD)

    • De novo in patient 2 with hypo/hyperreflexia, axonal neuropathy, tremors, tone abnormalities, limb weakness, short stature, motor delay, ID,

  • NM_001303256.3:c.394C>T Arg132Cys

PMID: 34664855 (2021)

  • c.1265A>G; NP_001290185.1: p.E422G - absent gnomAD, (aka) c.1079A>G Glu360Gly - de novo in 27month old w/ DD, dysphagia, abnormal MRI, suspected Leigh syndrome

FUNCTIONAL EVIDENCE:

Gene function: DNA-dependent ATPase that plays a role in chromatin remodeling, DNA repair and transcriptional regulation (summary by 32693025)

 

Source:

Clinical Validity Points Total

12

Source: 32693025, 36791574, 34664855

Clinical Validity Classification

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Definitive

Source:

Molecular Mechanism

Loss of function

Gain of function

Dominant negative

Unknown

Other

Unknown

Penetrance

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

 

Source:

Age of Onset

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(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

The MORC2 gene is associated with autosomal dominant MORC2-related neurodevelopmental syndrome and autosomal dominant Charcot-Marie-Tooth disease type 2Z (CMT2Z). The neurodevelopmental syndrome is characterized by developmental delay, intellectual disability, growth retardation, microcephaly, variable craniofacial dysmorphism. Additional features including neuropathy, hearing loss, abnormal brain MRI, and retinal pigentary abnormalities may also be observed. The vast majority of causative variants are de novo (PMID: 32693025). CMT2Z is characterized by axonal sensorimotor peripheral neuropathy (PMID: 26497905, 26659848, 27329773; ClinGen Curation ID: CCID:005407).

Case ID, Curator name, Date, Jira ticket link

AO 2106076994 02.07.2025