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Gene-disease assertions not curated here (add link or write note): Leukodystrophy, adult-onset, autosomal dominant (https://omim.org/entry/169500)

Disease

Primary microcephaly

Inheritance

Autosomal dominant

Prevalence

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen: Sufficient evidence for triplosensitivity, no evidence for haploinsufficiency for adult-onset autosomal dominant demyelinating leukodystrophy

GenCC: Microcephaly - Strong (Franklin and Invitae)

Clinical Validity Scoring Notes and points

Variant/Case Evidence:

c.455C>G p.Ala152Gly

  • Absent from gnomAD v4.

  • De novo in a male pt with microcephaly, DD/ID, feeding difficulties (patient 1, PMID: 32910914) (0.6pts)

p.Ser314_Thr497del

  • Maternally inherited in a female patient with microcephaly, pronounced and long philtrum, short nose, trigonocephaly, mild ID. Mother had OFC mother 50.5 cm (−2.5 SD), low educational level, long philtrum. Variant was de novo in mother. (patient 2, PMID: 32910914) (1pt)

c.97A>G p.Lys33Glu

  • Absent from gnomAD v4.

  • De novo in a female pt with microcephaly, prominent nasal root, protruding tongue, severe ID, pachygyria, thin corpus callosum, spasticity limbs, inability to walk, scoliosis, feeding difficulties, patent foramen ovale. Authors showed that p.Lys33Glu prevented proper formation of the lamina network (patient 3, PMID: 32910914) (1.1pts)

  • De novo in P1, a 1mo male pt with microcephaly, Simplified gyri large ventricles, Increased extraaxial space, seizures, severe DD, dysmorphic features, Recurrent lower respiratory tract infections, gastrostomy. ?pan-hypopit. PMID: 33033404 (0.6pts)

  • De novo in P9, 5-10yo male with microcephaly, Failure to thrive, poor feeding. Constipation. Stereotypical hand movements. Long palpebral fissures, hypertelorism, depressed broad nasal bridge. Pointed chin., Febrile Seizures, GDD. PMID: 33033404 (0.6pts)

  • De novo in P11. 5-10 yo female with microcephaly, Seizures, Hypoplasia/aplasia corpus callosum, Mild/Mod GDD PMID: 33033404 (0.6pts)

c.124C>T p.Arg42Trp

  • Absent from gnomAD v4.

  • De novo in a female patient with microcephaly, dysmorphic features, significant developmental delay, MRI abnormalities, seizures, suspected cortical visual impairment, feeding difficulties, G-tube, recurrent pneumonia. Additional duplication on microarray (15q25.3(85,811,682-86,140,453)x3 pat). Authors showed that p.Lys33Glu prevented proper formation of the lamina network (patient 4, PMID: 32910914) (1.1pts)

c.939+1G>A

  • Absent from gnomAD v4.

  • Adjacent exon is in-frame.

  • 3 affected sibs (one female and 2 male). All had microcephaly and some degree of developmental delay/ID, seizures, hypotonia, scoliosis. The two brothers had cortical visual impairment, feeding difficulties, G-tube, recurrent pneumonia. Father 15% mosaic for the mutation. One brother had an additional finding on microarray (17p13.3 (954,760-1,235,739)x3 (VOUS; CMA-ISCA)). Splice variant identified on trio WES. Mosaicism identified on further analysis. (patient 5-7, PMID: 32910914) (1 pt + 0.5 for sibs: 1.5pts)

c.97_99del p.K33del

  • Absent from gnomAD v4.

  • Identified in 2 unrelated affected pts (P2 and P3). De novo in 1 and unconfirmed in the other. PMID: 33033404 (0.6 pts + 0.1pts: 0.7pts)

c.269G>C p.R90P

  • De novo in a 15-20yo M with microcephaly, Mild/Mod GDD , Delayed speech and language development , Hydronephrosis. Failure to thrive Hypothyroidism. PMID: 33033404 (0.6pts)

Clinical Validity Points Total

8.4 (stopped here since moderate GDA was reached)

Clinical Validity Classification

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

At least moderate.

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function

Penetrance

 options

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

 options

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

congenital

Severity

 Options

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: PMID: 32910914, PMID: 33033404

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

 Examples

- 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

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