Inheritance

Autosomal recessive

Prevalence

 <1 / 1 000 000 (rare)

Source: Orphanet

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD

ClinGen Colon Cancer GCEP - limited 05/08/2017

GENCC (accessed 06/14/2023)
DEFINITIVE (TGMI|G2P) FANCONI ANEMIA COMPLEMENATION GROUP 2 (links to same OMIM as short stature, microcephaly, and endocrine dysfunction
STRONG (INVITAE) Short stature, micocephaly, and endocrine dysfunction
Strong (LMM) Short stature, micocephaly, and endocrine dysfunction

Clinical Validity Scoring Notes and points

Not done, rapid curation, using GENCC

Source:

Clinical Validity Points Total

N/A

Source:

Clinical Validity Classification

STRONG

Source: GenCC

Molecular Mechanism

Loss-of-function

PMID: 25728776 - Table 1 shows several NMD + variants in cmp het state in individuals with microcephalic primordial dwarfism:

• c.481C>T p.R161* (Exon 4, NMD+, 2 African alleles gnomAD). PMID: 25728776 compound het with p.Arg225* in patient P2. 

• c.673C>T p.R225* (exon 6, NMD+, 1 allele S. Asian gnomAD), found in P2. 

• Not counting this variant, though several submitters classify as P/LP in ClinVarc.25delC p.(His9Thrfs*8) - high frequency, 107/128924 European non-Finnish. 

PMID: 32524007

• c.628A>T p.K210* (exon 5, NMD+, absent gnomAD) - in trans with c.638+3A>G tested via microcephaly NGS panel.

Penetrance

(list source/PMID)

Not evaluated

Age of Onset

(list source/PMID)

Congenital

Severity

Not evaluated

Clinical Features

Primary microcephaly, facial gestalt (micrognathia, hypotelorism, long face with prominent chin, long and beaked nose, high nasal bridge, prominent philtrum, fine sparse hair, broad nasal tip, and deep-set eyes), developmental delay, neurological findings, primary gonadal failure. (PMID 32524007)

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 XRCC4 gene is associated with autosomal recessive short stature, microcephaly, and endocrine dysfunction (SSMED), which is characterised by primary microcephaly, facial gestalt (micrognathia, hypotelorism, long face with prominent chin, long and beaked nose, high nasal bridge, prominent philtrum, fine sparse hair, broad nasal tip, and deep-set eyes), developmental delay (PMID: 25728776, 32524007)

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 06/14/20223, https://broadinstitute.atlassian.net/browse/CIT-127