Disease | Short stature, microcephaly and endocrine dysfunction |
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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 | Variant/Case Evidence: Segregation Evidence: Case/Control Evidence: Experimental Evidence:Not done, rapid curation, using GENCC Source: |
Clinical Validity Points Total | N/A Source: |
Clinical Validity Classification | Expand |
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| title | Classifications (pts) |
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| Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed |
| STRONG Source: GenCC |
Molecular Mechanism | Expand |
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| Loss of function Gain of function Dominant negative Unknown Other |
| Loss-of-function / Gain of function / Dominant Negative 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 |
Penetrance | Expand |
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| Complete (100%) High (≥90%) Reduced (<90% and >10%) Low (≤10%) |
(list source/PMID) | Source:Not evaluated |
Age of Onset | Expand |
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| Congenital Pediatric Adolescent Adulthood Late adulthood |
(list source/PMID) | Congenital |
Severity | Expand |
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| 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. |
| Not evaluated |
Clinical FeaturesSources: | 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: | Expand |
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| - 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-dsiease relationship is limited |
| 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, | Jira Legacy |
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| server | System JIRA |
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| serverId | eee25142-2510-336f-918a-865682ebdf2e |
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| key | CIT-127 |
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