Gene-disease assertions not curated here (add link or write note):
FORMAT: HEADING 1 |
|---|
Inheritance | Autosomal recessive |
/ autosomal dominant / X-linked Rare Source: Orphanet |
Rapid or full curation? | |
ClinGen / GenCC / BabySeq / HGMD / OMIM | ClinGen - none. GenCC - Definitive for odontoleukodystrophy (illumina), Strong for AR Wiedemann-Rautenstrauch syndrome and leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome (Invitae) |
Clinical Validity Scoring Notes and points | Lumped several conditions together for scoring. Wiedemann-Rautenstrauch syndrome, tremor-ataxia with central hypomyelination (TACH), leukodystrophy with oligodontia (LO), Hypomyelination, hypodonita, and hypogonadotrophic hypogonadism (4H) syndrome. Reasons for lumping: All autosomal recessive conditions Shared variants and molecular mechanism. LOF variants (bold red text) observed across several exons and recurrent variants seen across the different phenotypes (c.1909+18G>A, p.Met852Val) Spectrum of phenotypes share some clinical characteristics: neurologic dysfunction (cerebellar, extrapyramidal, spasticity, cognitive), abnormal dentition, endocrine abnormalities (short stature, hypogonadotrophic hypogonadism), ocular abnormalities (myopia). Of note, severe end of the spectrum is Wiedemann-Rautenstrauch syndrome, which has a progeroid phenotype.
I scored the phenotypes separately at first and then made the assessment to lump after gathering the below evidence: Wiedemann-Rautenstrauch syndrome PMID: 38348603 (Khan 2024) |
38348603 - homozygous in family 1 and 2 with Wiedemann- Rautenstrauch syndrome, identified via WES. Per text parents were heterozygous. 2 CASES (deduct for consanguinity, 0 variant points), 1 SEGREGATION Clinical features include anophthalmia, bilateral talipes equinovarus, seizures, global developmental delay, inguinal hernia, microphthalmia, nystagmus, recurrent infections, severe failure to thrive, Sinus tachycardia, and vomiting, arthrogryposis multiplex congenita, motor delay, spasticity, and triangular face with prominent forehead, microphthalmia, bilateral epicanthal folds, low set ears, microstomia, short neck
c.1895G>T p.Cys632Phe - absent gnomad
|
38348603 - PMID: 30323018 (Paolacci 2018) |
PMID: 30323018 - variant found comp het in trans with two other variants, c.1909+22G>A and c.3337–11T>C. However, the text states that an unaffected father is HOM for the two intronic variants, which indicates these variants likely do not cause disease, and c.1909+22G>A has a very high MAF with 10 homozygotes in gnomAD v4. However, several clinical labs classify c.1909+22G>A as P/LP, and this paper performed cDNA sequencing which showed that c.1800c>t and c.1909+22g>a had a strong additive effect on splicing resulting in exon 14 (e14) skipping. Skipping scoring this variant because there is so much going on on the other allele.
PMID: 30450527 |
- Phenotype is progeriod(Lessel 2018) - cohort of patients with progeria who were negative for LMNA,underwent exome sequencing. |
allees 0.5 2 .5 0.5 2.5 - also known as neonatal progeroid syndrome; (SPECTRUM: tremor-ataxia with central hypomyelination (TACH) / leukodystrophy with oligodontia (LO) / Hypomyelination, hypodonita, and hypogonadotrophic hypogonadism (4H) syndrome. All share neurologic dysfunction (cerebellar, extrapyramidal, spasticity, cognitive), abnormal dentition, endocrine abnormalities (short stature, hypogonadotrophic hypogonadism)
|
Source:
PMID: 21855841 (Bernard et al. 2011)- shows variants in table , and per text there were “19 individuals belonging to 12 families were found to be homozygotes or compound hets”, therefore these variants are all cmp het or hom. The patient ancestry was broad and included French Canadian, White Americans, African Americans, French, Syrian, W. Europe and Guatemala. TACH Patient 1 c.1674C>G p.Phe558Leu (0.0008%, 15/1111990 European, REVEL 0.774) and c.3742insACC p.1248insThr (aka c.3739_3741dupACC p.Thr1247dup, absent gnomAD) - 0.5 + 0.5 POINTS = 1 POINT Patient 2-4 (family 2) HOM c.2015G>A p.Gly672Glu (0.0007% 14/1179896, European, REVEL 0.885) - 0.5x2=1 POINT, 2 AR SEG Patient 6 HOM c.2015G>A p.Gly672Glu (0.0007% 14/1179896, European, REVEL 0.885) - 0.5x2=1 POINT
4H Patient 7 c.2554A>G p.Met852Val (0.0004% 10/1179828 European, REVEL 0.698) c.2711-1G>A p.Arg873AlafsX878 (aka c.2617-1G>A, 0.003% 44/1179274 Euro, NMD+) = 0.5 + 2 = 2.5 POINTS Patient 8 c.2324A>T p.Asn775Ile (absent) and c.1114G>A p.Asp372Asn (0.0001% 5/1179980 European) - 0.5+0.5 = 1 POINT Patient 9 c.2830G>T p.Glu944X (0.0004%, 6/1111712 Eur) and c.3013C>T p.Arg1005Cys (13 alleles gAD). 2 + 0.5 = 2.5 POINTS Patient 10 c.2554A>G p.Met852Val (0.0004% 10/1179828 European, REVEL 0.698) and c.2711-1G>A p.Arg873AlafsX878 (aka c.2617-1G>A, 0.003% 44/1179274 Euro, NMD+) 0.5 + 2 = 2.5 POINTS Patient 11 France 4H c.4006C>T p.Gln1336X (absent gAD, NMD+) and c.1907C>A p.Ser636Tyr (absent gAD) - 2 + 0.5 = 2.5 POINTS
LO Patient 12-17 (Family X ) - HOM c.2003+18G>A p.Tyr637CysfsX650 aka c.1909+18G>A, same variant described in 27612211 with cDNA data showing premature stop. NMD+. 4 POINTS VARIANT, 5 SEG Patient 18 c.418C>T p.Arg140X (5 alleles total, NMD+) and c.2554A>G p.Met852Val (0.0004%, 101179828 Eur., REVEL 0.698) 2+0.5=2.5 POINTS Patient 19 HOM c.2171G>A p.Cys724Tyr (1 allele gAD, REVEL 0.578) 0.5x2= 1 POINT
|
Clinical Validity Points Total | 18 POINTS Source: 38348603, 21855841, 30450527, 27612211 |
Clinical Validity Classification | Expand |
|---|
| title | Classifications (pts) |
|---|
| Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed |
|
Source: Definitive |
Molecular Mechanism | Expand |
|---|
| Loss of function Gain of function Dominant negative Unknown Other |
| Loss of function |
/ Gain of function / Dominant NegativeCitation: PMID: 30450527, 27612211, 21855841 |
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) | Congenital/pediatric (PMID: 21855841, 38348603) to adulthood (32597037 Sources: PMID: 21855841, 38348603, 32597037 |
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. |
| Severe to moderate |
Clinical Features | Shared features in POLR3A: Neurologic dysfunction, typically predominated by motor dysfunction (progressive cerebellar dysfunction, and to a lesser extent extrapyramidal [i.e., dystonia], pyramidal [i.e., spasticity] and cognitive dysfunctions) Abnormal dentition (delayed dentition, hypodontia, oligodontia, and abnormally placed or shaped teeth) Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe
Wiedemann- Rautenstrauch :prenatal and postnatal growth retardation, short stature, a progeroid appearance, hypotonia, facial dysmorphology, hypomyelination leukodystrophy, and mental impairment POLR3-related Leukodystrophy: Includes several phenotypes that were previously described as different entities Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); Ataxia, delayed dentition, and hypomyelination (ADDH); Tremor-ataxia with central hypomyelination (TACH); Leukodystrophy with oligodontia (LO); Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC).
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 POLR3A gene is associated with a spectrum of autosomal recessive disorders that have clinical overlap. These include Wiedemann- Rautenstrauch syndrome, a severe condition characterized by prenatal and postnatal growth retardation, short stature, a progeroid appearance, hypotonia, facial dysmorphology, hypomyelination leukodystrophy, and mental impairment (PMID: 38348603, 21855841, 30450527,). POLR3A-related leukodystrophies are characterized by varying combinations of neurologic dysfunction, abnormal dentition, endocrine abnormalities, and ocular abnormalities (PMID: 22855961, 21855841). The age of onset can range from birth to adulthood (PMID: 21855841, 38348603, 32597037). |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza, D-211113280-BH-4026-P-A, 02/15/2024 |