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Gene-disease assertions not curated here (add link or write note): did not curate the AD hearing loss phenotype, but note that these variants cluster to exon 21, and Exon 21 containing isoform the only transcript in the developing cochlea (McNeill et al., 2020).
TABLE 1 IN 33500540 HAS A GOOD SUMMARY OF CASES
Disease | Kilquist syndrome |
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Inheritance | Autosomal recessive |
Prevalence | Source: |
Rapid or full curation? | |
ClinGen / GenCC / BabySeq / HGMD / OMIM | No ClinGen Curations, 3 strong curations from Invitae (AD hearing loss, AD Delpire-McNeill syndrome, AR Kilquist syndrome) |
Clinical Validity Scoring Notes and points | AR Kilquist syndrome PMID: 34797034 reports child with respiratory distress, thick secretions in the airway, midgut malrotation and GERD. Recurrent staph infection. Global DD, severe-profound bilateral sensorineural hearing loss. Two variants in trans: c.1536+4_1536+7del (RNA seq showed del exons 8 and 9) and c.940C>T p.Q314* (https://gnomad.broadinstitute.org/variant/5-128114275-C-T?dataset=gnomad_r4 , 2 alleles, NMD+) 2x2 LOF POINTS = 4 VARIANT POINTS No phenotype in the heterozygous parents. Supports LOF is mechanism for AR only. Authors propose that the heterozygous de novo syndrome described in severe neurodev patients from McNeill et al., 2020 might be due to a dominant negative effect Table 1 also summarizes additional AR cases: Stodberg 1 (PMID: 32754646)- c.1431delT (Phe477Leufs*48) and 2006-1G>A and sibling with the same variants. Both considered LOF. 2 x 2 LOF variants = 4 points Kilquist (Macnamara et al 2019 PMID: 30740830) - 22 kb deletion (exons 2-6) and UPD (ie - results in a 22kb deletion) 2x2 LOF variants = 4 points. Bilal Shamshi family 1 and 2 (PMID: 33500540) - per the original paper, both families have homozygous c.2617-2A>G. Parents confirmed het carriers. Counting 1 proband in case of shared ancestry, 2x2 LOF = 4 POINTS + 2 AR SEGREGATIONS
Experimental NKCC1 has been demonstrated to play a central role in neurogenesis and the excitatory-inhibitory GABA switch (Delpire et al., 1999) PMID: 10369265 32658972 - Analysis of SLC12A2 expression in foetal brain at 16-18 weeks post-conception revealed high expression in radial glial cells, compatible with a role in neurogenesis. 1 POINT EXPRESSION Exon 21 containing isoform the only tran-script in the developing cochlea (McNeill et al., 2020), which is likely why exon 21 variants cause nonsyndromal deafness and variants in other exons cause a more severe neurdeve disorder.
Source: |
Clinical Validity Points Total | >12 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 |
| Definitive (replicated 2019-2021) Source: |
Molecular Mechanism | Expand |
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| Loss of function Gain of function Dominant negative Unknown Other |
| Loss of function See clinical validity scoring, all LOF PMID: 34797034, 32754646, 30740830, 33500540 |
Penetrance | Expand |
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| Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) |
(list source/PMID) | |
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. |
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Clinical Features | PMID: 34797034 reports child with respiratory distress, thick secretions in the airway, midgut malrotation and GERD. Recurrent staph infection. Global DD, severe-profound bilateral sensorineural hearing loss. Additional features table 1:
Sources: |
HPO Terms https://hpo.jax.org/app/ | |
Gene SOPs & Notes | |
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 |
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Case ID, Curator name, Date, Jira ticket link | Andrea Oza E3800892000, 09.23.24 |
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