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Gene-disease assertions not curated here (add link or write note):
Disease | |
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Inheritance | Autosomal dominant |
Prevalence | 1-9 / 100 000 Source:ORPHA:606 |
Rapid or full curation? | |
ClinGen / GenCC / BabySeq / HGMD / OMIM | ClinGen - none. GenCC - Strong (Invitae), BabySeq - none. HGMD - 1 entry for repeat expansions. |
Clinical Validity Scoring Notes and points | Liquori 2001 (PMID: 11486088) - mapped the MD2 locus and used positional cloning to identify the DM2 mutation. Per text, all 51 affected individuals in 6 DM2 families were found to have expanded alleles |
. (confirmed by Southern and PCR, counting max 3 POINT SEGREGATION) Sequencing revealed a complex repeat motif ( TG)n( TCTG)n(CCTG)n. In controls this tract ranged from 104-176 basepairs. The largest repeat tract in normal controls had 26 CCTG repeats with two interruptions. Three families with a total of 6 individuals with expansions of the CCTG repeat (fig 1D), 3 segregations. Expanded alleles ranged from 75-1100 CCTG repeats ( |
>10 individuals shown here 6 families with expansions, 1 proband each family 0. |
5x10 5x6 variant points, 3 VARIANT POINTS). Bachinski 2003 (PMID: 12970845) |
. The normal alleles. Source: - 17 kindreds of European origins link to the locus. Fig 2 shows a family with expansion found in RP-PCR. Counting segs based on RP-PCR results: III:2 proband, segregations in III:3, III:4, IV:2, II:1 (obligate), II:3, II:6. Total of 6 segs. Wei 2018 PMID:29735719. Immunofluorescence of muscle from DM2 patients and controls found that CNBP localized in cytoplasm in control tissue whereas it localized primarily ni membrane of DM2 fibers. Animal model - CNBP knockout mouse had muscle atrophy at young age, heterozygous mice had severe muscle loss only at advanced age. Since the KO mice aren’t true replications of the expanded allele, not scoring. Functional alteration in patient cells - 1 POINT EXPERIMENTAL Raheem 2010 PMID: 20971734 - In differentiating myoblasts, in patients with DM2, ZNF9 was abnormally expressed. There was overall reduction in mRNA and protein levels. The subcellular localization was more membrane bound. Splice variant analysis indicated retention of intron 3. Functional alteration in non-patient cells 0.5 points experimental. |
Clinical Validity Points Total |
Source: Triplet Repeat 12 points genetic (max allowed) + 1.5 points experimental |
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 |
| Definitive Source: 11486088, 12970845, 29735719, 20971734 |
Molecular Mechanism | Expand |
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| Loss of function Gain of function Dominant negative Unknown Other |
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Loss of function / Gain of function / Dominant Negative
Short tandem repeats ONLY (no other variant type reported) STR expansion - complex motif (TG)n(TCTG)n(CCTG)n . Other labs report by the basepair size; however, we will get CCTG repeat size. It is the expansion of this tract that has been associated with disease. Literature: GeneReviews PMID: 20301639 - normal ≤30 uninterrupted CCTG repeats OR 11-26 CCTG repeats with any GCTC or TCTG interruptions. Unknown significance (normal vs. mutable) 27-29 CCTG repeats. Mutable normal (premutatio) ~30-~54 CCTG repeats. Unknown significance (premutation vs pathogenic) ~55-74 ~55-74 CCTG repeats. Pathogenic ~75-11,000 CCTG repeats. “Due to variability in the TG and TCTG portions of the repeat tract, a total repeat size in base pairs is frequently reported and CCTG repeat length is often estimated [Liquori et al 2001, Liquori et al 2003, Radvanszky et al 2013, Mahyera et al 2018].”
gnomAD Normal ≤ 54, Pathogenic ≥ 55 Stripy - normal ≤29, intermediate 30-55, pathogenic ≥55 Not in the Mayo paper https://docs.google.com/spreadsheets/d/189Ph82ZPDhHwgTtmmPpCItan8boniGIL/edit#gid=1020718149 Other labs: labcorp - pathogenic is over 75. Athena - Normal: Less than 177 base pairs. Mayo (sends to Athena). Sample report shows Normal (<177 base pairs), Borderline (177-372 base pairs), Positive (>372 base pairs) Fulgent, not provided. GeneDx - Normal alleles have 26 or less CCTG repeats and disease alleles have 75 or more repeats. Disease alleles can contain more than 11,000 repeats, with an average of 5,000 repeats.1
Liquori 2001 (PMID: 11486088) - largest normal was 26 CCTG repeats, smallest pathogenic reported to be 75 CCTG repeats. Sukel 2018 29588063 - Polish controls had 110-228bp alleles. For confirmed probands. Majority of control alleles were 110-158bp. Mahyera 2018 29973908 - Two premutation families studied, results support that premutation range of unstable CCTG stretches lie between 25-75 repeats. Botta 2021 PMID: 34234810 - Italian cohort. DM2 molecular diagnosis confirmed in 187/570 samples analyzed with 25 different alleles ranging from 108 to 168bp. They identified the presence of an uninterrupted CCTG tract below 26 repetitions which is considered The general structure of the normal repeat motif is (TG)14−26(TCTG)7−11(CCTG)5−9(NCTG)3−5(CCTG)4−8. Fig 5 shows premutations, all range from 37 to 55, though these individuals do appear to have some clinical features. INTERRUPTIONS:
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Penetrance | Expand |
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| Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) |
(list source/PMID) | Moderate / Low Source: 11486088 |
Age of Onset | Expand |
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| Congenital Pediatric Adolescent Adulthood Late adulthood |
(list source/PMID) | Adulthood, late adulthood |
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. |
| Moderate |
Clinical Features | myotonia and muscle dysfunction (proximal and axial weakness, myalgia, and stiffness) cataracts cardiac conduction defects insulin-insensitive type 2 diabetes mellitus Sources: PMID: 20301639 |
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 variantshort tandem repeat expansions are the only known variant associated with disease, see mol. mech section |
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-dIsease relationship is limited |
| The CNBP gene is associated with autosomal dominant myotonic dystrophy type 2, which is characterized by myotonia and muscle dysfunction, cataracts, cardiac conduction defects, and type 2 diabetes. It is caused by a short tandem repeat expansion. Age of onset is in adulthood, severity can vary, and reduced penetrance has been observed (PMID: 20301639, 11486088) |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza 09.29.2023 | Jira Legacy |
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| server | System JIRA |
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| serverId | eee25142-2510-336f-918a-865682ebdf2e |
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| key | BCL-168 |
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