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| Intellectual disability v9.198 | TSEN34 |
Ida Ertmanska changed review comment from: PMID: 20952379 Namavar et al., 2011 Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only. Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical. PMID: 27370523 Balbi, Taicher & Litman, 2016 Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details. Functional evidence: PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023 Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability. Additional info: Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing). This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).; to: PMID: 20952379 Namavar et al., 2011 Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only. Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical. PMID: 27370523 Balbi, Taicher & Litman, 2016 Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details. Functional evidence: PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023 Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability. Additional info: Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing). This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 16th Dec 2025). |
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| Intellectual disability v9.196 | TSEN34 |
Ida Ertmanska changed review comment from: PMID: 20952379 Namavar et al., 2011 Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only. Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical. PMID: 27370523 Balbi, Taicher & Litman, 2016 Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details. Functional evidence: PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023 Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability. Additional info: Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing). This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).; to: PMID: 20952379 Namavar et al., 2011 Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only. Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical. PMID: 27370523 Balbi, Taicher & Litman, 2016 Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details. Functional evidence: PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023 Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability. Additional info: Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing). This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025). |
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| Intellectual disability v9.196 | TSEN34 |
Ida Ertmanska changed review comment from: PMID: 20952379 Namavar et al., 2011 Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only. Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical. No mention of cognitive ability. PMID: 27370523 Balbi, Taicher & Litman, 2016 Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details. Functional evidence: PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023 Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability. Additional info: Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing). This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).; to: PMID: 20952379 Namavar et al., 2011 Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only. Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical. PMID: 27370523 Balbi, Taicher & Litman, 2016 Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details. Functional evidence: PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023 Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability. Additional info: Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing). This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025). |
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| Intellectual disability v3.1561 | DALRD3 |
Konstantinos Varvagiannis changed review comment from: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910). Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant. Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger. WES guided by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents. DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR It's DALR anticodon-binding domain is similar to those found in arginyl-tRNA synthetases RARS1/2. As the authors demonstrate, and (better) summarized in OMIM, its product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. In particular, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs. In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS2). Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lysates, with severe reduction (/loss) of m3C modification of the specific arginine tRNAs, which was not observed for other tRNAs (eg. tRNA-Ser-UGA) or controls. These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele. As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc). Consider inclusion in the current panel with amber rating. Sources: Literature; to: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910). Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant. Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger. WES in both followed by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents. DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR As the authors demonstrate, and (better) summarized in OMIM, its product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. In particular, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs. In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS2). Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lysates, with severe reduction (/loss) of m3C modification of the specific arginine tRNAs, which was not observed for other tRNAs (eg. tRNA-Ser-UGA) or controls. These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele. As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc). Consider inclusion in the current panel with amber rating. Sources: Literature |
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| Intellectual disability v3.1561 | DALRD3 |
Konstantinos Varvagiannis gene: DALRD3 was added gene: DALRD3 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: DALRD3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DALRD3 were set to 32427860 Phenotypes for gene: DALRD3 were set to ?Developmental and epileptic encephalopathy 86, # 618910 Penetrance for gene: DALRD3 were set to Complete Review for gene: DALRD3 was set to AMBER Added comment: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910). Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant. Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger. WES guided by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents. DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR It's DALR anticodon-binding domain is similar to those found in arginyl-tRNA synthetases RARS1/2. As the authors demonstrate, and (better) summarized in OMIM, its product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. In particular, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs. In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS2). Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lysates, with severe reduction (/loss) of m3C modification of the specific arginine tRNAs, which was not observed for other tRNAs (eg. tRNA-Ser-UGA) or controls. These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele. As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc). Consider inclusion in the current panel with amber rating. Sources: Literature |
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| Intellectual disability v2.556 | RARS2 | Sarah Leigh Publications for gene: RARS2 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | RARS2 | BRIDGE consortium edited their review of RARS2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | RARS2 | BRIDGE consortium edited their review of RARS2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | RARS2 | BRIDGE consortium reviewed RARS2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||