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Andrea Oza

Andrea Oza

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Table of Contents

Gene-disease assertions not curated here (add link or write note):

Disease

FORMAT: HEADING 1

POLR3A-related disorders

Inheritance

Autosomal recessive

/ autosomal dominant / X-linked

Prevalence

Expand
titlePossible sources

Orphanet

Medline Plus Genetics

 

 Rare

Source: Orphanet

Rapid or full curation?

  •  Rapid
  •  Full

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)

  • c.2456C>T p.Pro819Leu - absent gnomad. 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. One family with Wiedemann- Rautenstrauch syndrome, consanguineous. 1 CASE (0 variant points = 0.5-0.5 for consanguinity), 1 SEG

PMID: 30323018 (Paolacci 2018)

  • c.2474C>G p.S825* - 1 allele gnomad, NMD+ - 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 (Lessel 2018) - cohort of patients with progeria who were negative for LMNA,underwent exome sequencing.

  • Patient 1 with c.3337-5T>A (6 alleles gnomAD, splice AI 0.02 but per text cDNA shows exon skipping of exon 26, in frame) in trans with c.3337-1G>A (2

allees

  • alleles gnomad, SpliceAI 0.99). Exon is in frame.

0.5

  • 1 +

2

  • 1 = 2

.5

  • VARIANT POINTS

  • Patient 2 with c.3337-5T>A and p.R254* (0.005%, 78/1180036 European chr).

0.5

  • 1 + 2 =

2.5

  • 3 VARIANT POINTS

PMID: 27612211

-

(Jay 2016)

  • Proband with Wiedemann-Rautenstrauch

syndrome, also known as neonatal progeroid

  • syndrome,

described in an individual

  • with two variants in trans: 1) c.1909+18G>A (2 alleles gnomAD, paper states previous RNA studies demonstrated a premature stop with impact p.Y637Cfs23) and c.2617C>T; p.(R873*), scoring as two NMD+ variants, 2+2 = 4 POINTS

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), ocular abnormalities (myopia)

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

VIII WUSA 4H

    • c.2554A>G p.Met852Val

F 12

    • (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

F 1 þ þ þ þ þ þ þ þ N/A

    • (absent gAD, NMD+) and c.1907C>A p.Ser636Tyr

12 X Syria

    • (absent gAD) - 2 + 0.5 = 2.5 POINTS

  • LO

    • Patient 12-17 (Family X ) - HOM c.2003+18G>A p.Tyr637CysfsX650

  • Patient 13

  • Patient 14 M 13 þ þ þ þ 23 þ N/A 28 13 X Syria LO c.2003þ18G>A p.Tyr637CysfsX650 F 12 þ þ þ þ þ 20 þ N/A 14 X Syria LO c.2003þ18G>A p.Tyr637CysfsX650

    • Clinical Validity Points Total

    Source:

      • 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
    titleClassifications (pts)

    Definitive (12pts)

    Strong (12pts)

    Moderate (7-11pts)

    Limited (0.1-6pts)

    No genetic evidence

    Refuted

    Disputed

    Source:

    Definitive

    Molecular Mechanism

    Expand
    titleMechanisms

    Loss of function

    Gain of function

    Dominant negative

    Unknown

    Other

    Loss of function

    / Gain of function / Dominant Negative

    • p.R254* - PMID: 30450527

    • c.2617C>T; p.(R873*) - PMID: 27612211

    • p.Glu944X p.Gln1336X and p.Arg140X in PMID:21855841

    Citation: PMID: 30450527, 27612211, 21855841

    Penetrance

    Expand
    titleoptions

    Complete (100%)

    High (≥80%)

    Moderate  (<80% and >20%)

    Low (≤20%)

    (list source/PMID)

    Source:

    Age of Onset

    Expand
    titleoptions

    Congenital

    Pediatric

    Adolescent

    Adulthood

    Late adulthood

    (list source/PMID)

    Congenital/pediatric (PMID: 21855841, 38348603) to adulthood (32597037

    Sources: PMID: 21855841, 38348603, 32597037

    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.

    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:

    • 38348603, 21855841

    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
    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 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