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Disease

KLHL20-related neurodevelopmental disorder

Inheritance

Autosomal dominant

Prevalence

Expand
titlePossible sources

Orphanet

Medline Plus Genetics

Unknown, curating as common/non-specific.

Source:

Rapid or full curation?

  •  Rapid
  •  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

No reported GDA in ClinGen, OMIM, GenCC, or BabySeq.

HGMD reports 3 DM variants, all associated with Intellectual disability, autistic features and dysmorphic facial features.

Clinical Validity Scoring Notes and points

Variant/Case Evidence

c.1069G>A p.Gly357Arg

  • Absent from GnomAD v4.

  • PMID 36214804: Seen de novo in 11 patients, see Table 1 and supplement for detailed clinical info.

    • Where data was available, all patients had normal birth weight, birth length, and birth OFC.

    • 2/11 tall stature, 2/11 microcephaly, 5/11 hypertelorism, 3/11 micrognathia, 3/11 bulbous nasal tip, 5/11 full lower lip, 4/10 large ears, 2/11 skull deformity, 3/11 strabismus, 3/11 hyphosis, 1/11 scoliosis, 2/10 pectus excavatum, 3/11 distal joint laxity, 2/11 vascular anomalies, 1/11 cardiac anomalies, 2/11 GERD, 9/11 chronic constipation, 5/11 drooling, 11/11 ID, 3/10 developmental regression, 11/11 seizures, 5/11 truncal hypotonia, 4/11 dystonia or spasticity, 8/10 stereotypic movements, 4/9 abnormal MRI, 9/11 ASD, 8/10 hyperactivity, 7/11 aggression

    • Ages ranged from 6-25yo

    • P1: trio genome, also carried a 2Mb deletion including SHOX. Authors believe this explains the patiant’s patient's short stature. 0.1 points (reducing due to additional findings)

    • P2: trio exome, also carried a rare maternally inherited missense variant was identified in ATP1A2 (NM_000702.4:c.1148G>A), previously reported as pathogenic. 0.1 points (reducing due to additional findings)

    • P3: Trio exome. 0.6 points.

    • P4: Targeted testing of KLHL20 recurrent variant based on phenotypic resemblance to P3. Confirmed de novo also using targeted testing. 0.1 points (reducing due to targeted testing)

    • P5: Trio exome. 0.6 points.

    • P6: Trio exome. 0.6 points.

    • P7: Trio exome. 0.6 points.

    • P8: Trio exome. 0.6 points.

    • P5P9: Trio exome. 0.6 points.

    • P10: Trio exome. 0.6 points.

    • P11: Singleton exome, also carried a rare nonsense variant in TNRC18 (NM_001080495.2:c.1756C>T). 0.1 points (reducing due to singleton exome)

  • PMID 33057194

    • HGMD “Developmental disorder; [De novo]. Potentially multiple de novo variants present. See Supplementary Table 1. [B:1:173726216:G:A:hg19]”

    PMID 35982159

    • HGMD “Autism; RUMC cohort. See Supplementary Data 3. [B:1:173726216:G:A:hg19]” Seen de novo in rumc_patient_1599 (supplemental table 1), patient from Radboud University Medical Center with unexplained ID.

  • PMID 35982159

    • SPARK cohort, identified de novo in a female patient (rumc_patient_1599). See Supplementary Data 3. Likely the same individual as PMID 33057194.

c.1214G>A p.Ser405Asn

  • PMID 36214804: Seen in P12. 22-year-old adult male patient with moderate ID, behavioral difficulties and hyperactivity, and dysmorphic features (more detail in supplement). Variant identified on trio exome, confirmed de novo. 0.6 points.

  • PMID 35982160

    • Supplementary table 5, identified de novo in a patient with autism. 0 points.

  • PMID 35982159

    • SPARK cohort. Identified de novo in a male patient with autism. See Supplementary Data 1 0 points.

c.1262A>G p.Gln421Arg

  • PMID: 36214804: Seen in P13. 12-year-old boy with a developmental and epileptic encephalopathy (more clinical info in supplement). Identified on targeted capture and sequencing of candidate epilepsy genes. Sanger sequence analysis of parents confirmed that the variant occurred de novo. 0.6 points.

c.1777G>T p.Gly593Trp

  • PMID: 36214804: Seen in P14. a 23-year-old female who presented with neonatal convulsions at day 15 (more clinical info in supplement). Trio exome, de novo. 0.6 points.

Segregation Evidence: N/A

Case/Control Evidence: N/A

Experimental Evidence: Not reviewed

Clinical Validity Points Total

6.4 points

Clinical Validity Classification

Expand
titleClassifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Moderate

Molecular Mechanism

Expand
titleMechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Unknown

Penetrance

Expand
titleoptions

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:Unknown

Age of Onset

Expand
titleoptions

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

Expand
titleOptions

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

Mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity, and subtle dysmorphic facial features

Sources: PMID: 36214804

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

All reported variants in PMID: 36214804 cluster in the Kelch-type β-propeller domain of the KLHL20 protein.

N/A

Curation Summary

Expand
titleExamples

- 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 KLHL20 gene is associated with autosomal dominant KLHL20-related neurodevelopmental disorder, which is characterized by global developmental delay, mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity. Some individuals with this disorder also have chronic constipation, aggressive behavior, and distinct facial features or skeletal features (PMID: 36214804).

Case ID, Curator name, Date, Jira ticket link

SDSM-25L

Areesha Salman 7/2/2024

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