Disease | Autosomal dominant intellectual disability | |
|---|
Inheritance | autosomal dominant | |
Prevalence | Common or non-specific Source: | |
Rapid or full curation? | | |
ClinGen / GenCC / BabySeq / HGMD / OMIM | ClinGen has a curation for AD distal hereditary motor neuronopathy (https://search.clinicalgenome.org/kb/genes/HGNC:2961), as well as dosage sensitivity curations. ClinGen dosage sensitivity curations indicate no evidence for triplosensitivity or haploinsufficiency. From ClinGen’s dosage sensitivity curation: “Variants in the N-terminal stem domain are more commonly described in patients with autosomal dominant neuromuscular disease (e.g. autosomal dominant axoxinal Charcot-Marie-Tooth disease type 2O, lower extremity-predominant spinal muscular atrophy-1), whereas variants in the C-terminal motor domain are more commonly reported in patients with intellectual disability (ID) and malformations in cortical development (MCD)”. Not in BabySeq. GenCC: 3 submissions for autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures (definitive, strong, supportive). 1 submission for autosomal dominant non-syndromic intellectual disability (supportive). 2 submissions for Charcot-Marie-Tooth disease axonal type 2O (strong, supportive). 3 submissions for intellectual disability, autosomal dominant 13 (definitive, strong, strong). 1 submission for distal hereditary motor neuronopathy (definitive by ClinGen).
OMIM: AD Charcot-Marie-Tooth disease, axonal, type 2O AD Cortical dysplasia, complex, with other brain malformations 13 AD Spinal muscular atrophy, lower extremity-predominant 1
| |
Clinical Validity Scoring Notes and points | Variant/Case Evidence (7 points) DYNC1H1 p.del659-662 - 0.6 points Not in GnomAD v4. PMID: 23603762, Patient P144, 15yo with microcephaly, bedridden, spastic tetraplegia, early onset epilepsy, MRI findings. De novo. Variant identified through targeted screening of DYNC1H1, TUBG1, KIF2A, and KIF5C (Supp Table 4)
DYNC1H1 p.K129I - 0.6 points Not in GnomAD v4. REVEL = 0.390. PMID: 23603762, Patient P582, 10yo with severe ID, late onset epilepsy, MRI findings. De novo. Variant identified through targeted screening of DYNC1H1, TUBG1, KIF2A, and KIF5C (Supp Table 4).
DYNC1H1 p.K3336N - 1.1 points Not in GnomAD v4. REVEL = 0.540. PMID: 23603762, Patient P122, 12yo with microcephaly, bedridden, spastic tetraplegia, early onset epilepsy, foot deformities, MRI findings. De novo. Variant identified on exome. (Supp Table 4). Functional studies and showed that this variant showed a significant reduction in microtubule binding affinity compared to WT control (Fig 3d).
DYNC1H1 p.R3384Q- 1.1 points Not in GnomAD v4. REVEL = 0.395 PMID: 23603762, Patient P217, 10yo with microcephaly, bedridden, spastic tetraplegia, early onset epilepsy, foot deformities, MRI findings. De novo. Variant identified on exome. (Supp Table 4). Functional studies and showed that this variant showed a significant reduction in microtubule binding affinity compared to WT control (Fig 3d).
DYNC1H1 p.R1567Q- 0.6 points Not in GnomAD v4. REVEL = 0.508 PMID: 23603762, Patient P398, 7yo with severe ID, no epilepsy and normocephalic, foot deformities, MRI findings. De novo. Variant identified on exome. (Supp Table 4).
DYNC1H1 p.R3344Q- 1.2 points Not in GnomAD v4. REVEL = 0.439 PMID: 23603762, Patient P535, 5yo with severe ID and autistic features, Lennox Gastaut and normocephaly, MRI findings, De novo. Variant identified through targeted screening of DYNC1H1, TUBG1, KIF2A, and KIF5C (Supp Table 4). PMID: 23603762, Patient 574C, 3 yo with moderate ID and focal seizures, MRI findings. De novo. Variant identified through targeted screening of DYNC1H1, TUBG1, KIF2A, and KIF5C (Supp Table 4).
DYNC1H1 p.R1962C - 0.6 points Not in GnomAD v4. REVEL = 0.441 PMID: 23603762, Patient 360J, 19yo with severe ID and focal seizures, MRI findings. De novo. Variant identified through targeted screening of DYNC1H1, TUBG1, KIF2A, and KIF5C (Supp Table 4).
DYNC1H1 p.Glu1518Lys - 0.6 points Not in GnomAD v4. REVEL = 0.573 PMID: 22368300 - 51yo female with severe ID (never been able to walk or speak), congenital clubfeet, epileptic seizures, short stature, head circumference in 2nd percentile. dysmorphic features. wide lateral and third ventricles on CT scan. De novo p.Glu1518Lys variant identified on trio exome sequencing. Non-paternity and sample mixup were excluded.
DYNC1H1 p.His3822Pro - 0.6 points Not in GnomAD v4. REVEL = 0.718 PMID: 22368300 - male with hypotonia, developmental delay, moderately severe ID, mild dysmorphic features. His3822Pro variant was found on trio exome sequencing, de novo. Non-paternity and sample mixup were excluded. PMID: 21076407 - same case as above. PMID 21076407 is the original report.
Segregation Evidence: Case/Control Evidence: Experimental Evidence: Other papers not yet reviewed: 26395554 28196890 29243232, 34803881, 32788638 (likely many others). | |
Clinical Validity Points Total | 7 points so far (incomplete) Source: | |
Clinical Validity Classification | Expand |
|---|
| title | Classifications (pts) |
|---|
| Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed |
| Source: | |
Molecular Mechanism | Expand |
|---|
| Loss of function Gain of function Dominant negative Unknown Other |
| Loss of function / Gain of function / Dominant Negative | |
Penetrance | Expand |
|---|
| Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) |
(list source/PMID) | Source: | |
Age of Onset | Expand |
|---|
| Congenital Pediatric Adolescent Adulthood Late adulthood |
(list source/PMID) | | |
Severity | Expand |
|---|
| 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: | |
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 | Expand |
|---|
| - 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 DYNC1H1 gene is associated with autosomal dominant syndromic intellectual disability. It is primarily caused by de novo missense variants, although some familial cases and other variant types have been reported (PMID: 22368300, 23603762, 34803881). The clinical characteristics are variable. Affected individuals may present with infantile spasms, epileptic encephalopathy, microcephaly, dysmorphic features, intellectual disability, or developmental delay. The DYNC1H1 gene has also been shown to be associated with distal hereditary motor neuropathy, and some individuals have features that overlap between the two conditions (PMID: 32656949, 32788638). | |
Case ID, Curator name, Date, Jira ticket link | D-141007478-BH-4001-P-A, Areesha Salman, 2/18/24 | |