Inheritance

Autosomal recessive

Prevalence

 unknown

Source: ORPHA:88616

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - Dosage sensitivity score 30 (associated w/ AR phenotype). GenCC - strong (invitae), moderate (Ambry), not curated by babyseq. HGMD variants reviewed are in clinical validity scoring.

Clinical Validity Scoring Notes and points

1. c.169_172delCACT p.(His57Valfs*11) - 0.019% (22/74860) African / African American chr. NMD+

   1. PMID: 24501276 found homozygous in a large Yemeni family. While only 1 parent from KSA branch was genotyped, since unaffected indivudal IV-11 is wt/wt, I am going to assume III-1 is a het carrier. 6 affected and 6 unaffected segregations in generation IV. 2 POINTS NMD+ VARIANT

2. c.397C>T p.Q133 - NMD- skipping for now

3. c.282_286delAGATA p.(Gln94Hisfs*6) - 0.0001% (1/86218) S Asian chr in gAD v4. NMD+

   1. PMID: 24626631 - found homozygous in family LFKK1. 3 affected segs and 1 unaffected seg. 2 POINTS NMD+ VARIANT

4. c.178dupG p.(Glu60Glyfs*11) - absent gnomAD, NMD+,

   1. PMID: 32439618 - found in two siblings with similar phenotype from PMIDs 24501276 and 24626631. Parents are het carriers. 2 POINTS NMD+ VARIANT

SEGREGATIONS: 9 affected, 7 unaffected, 3 POINTS SEGREGATION

Source:

Clinical Validity Points Total

9

Source:

Clinical Validity Classification

At least moderate, stopped at 9 points

Source: 24501276, 24626631, 32439618

Molecular Mechanism

Loss of function

See variants (3 NMD+) scored in clinical validity scoring.

Source: 24501276, 24626631, 32439618

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Congenital

Severity

Clinical Features

Cognitive impairment, developmental delay, hypotonia, seizures, characteristic facial features (large eyes, depressed nasal bridge, short upturned nose, long philtrum, thin lips, incomplete syndactyly (PMID: 24501276, 24626631)

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 METTL23 gene is associated with autosomal recessive METTL23-related intellectual developmental disorder, which is characterized by intellectual disability, developmental delay, hypotonia, seizures, characteristic facial features including large eyes, depressed nasal bridge, short upturned nose, long philtrum, and thin lips(PMID: 24501276, 24626631).

Case ID, Curator name, Date, Jira ticket link

D-201116014-BH-4042-P-A, ANDREA OZA 01.30.2024