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Genomic screening in children: BabyScreen+ v0.96 CEL Seb Lunke Mode of pathogenicity for gene: CEL was changed from Other to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Genomic screening in children: BabyScreen+ v0.95 CEL Seb Lunke Added comment: Comment on mode of pathogenicity: Dominant Negative Gain-of-Function experimentally established
Genomic screening in children: BabyScreen+ v0.95 CEL Seb Lunke Mode of pathogenicity for gene: CEL was changed from Other to Other
Genomic screening in children: BabyScreen+ v0.94 CEL Seb Lunke Mode of pathogenicity for gene: CEL was changed from to Other
Genomic screening in children: BabyScreen+ v0.93 CEL Seb Lunke Marked gene: CEL as ready
Genomic screening in children: BabyScreen+ v0.93 CEL Seb Lunke Gene: cel has been classified as Green List (High Evidence).
Genomic screening in children: BabyScreen+ v0.93 CEL Seb Lunke Publications for gene: CEL were set to 24062244; 21784842; 19760265; 18544793; 17989309; 16369531; 29233499; 27650499
Genomic screening in children: BabyScreen+ v0.92 CEL Seb Lunke changed review comment from: Specific CEL gene variants have been associated with MODY8, and potentially hereditary chronic pancreatitis, in 5 families to date (PMID:37726640). All families have single base frame shift deletions in the VNTR (Variable Number of Tandem Repeats) region of the last exon (exon 11) of the CEL gene, specifically in the first (DEL1), fourth and fifth (DEL4,5) repeat of the VNTR region (GRCh38 chr9:133,071,168-133,071,332).

Experimental evidence supports a Gain of Function, dominant negative mechanism of pathogenicity, in which certain frameshift variants cause the resulting protein to from toxic cellular aggregates (29233499). Crucially, an extended number of frameshifted repeats seem to be required to facilitate the formation of these aggregates (27650499, 38483348, 33862081). This is likely due to the increased presence of cysteine residues facilitating di-sulphide bonds, and the decreased presence of Threonine residuce that undergo O-glycosylation which is necessary for protein secretion. In addition, heterozygous NMD variants are common in gnomAD v4 for this gene, further arguing against dominant LoF as a pathogenic mechanism despite the potential for late onset and reduced penetrance.

Importantly, both more distal frameshift deletions, distal single base insertions (beyond repeat 7), and frameshift variants that result in a premature termination codon in the same repeat, have no strong evidence for pathogenicity to date as they do not result in toxic protein aggregation (38483348, 33862081). Some insertions in the proximal VNTR region, in particular in the first and fourth repeat (INS1, INS4), may confer an increased risk of pancreatitis, but evidence so far remains inconclusive (PMID:38483348). More distal single base insertions (beyond repeat 7) and distal deletions have been described as likely benign.

From a technical perspective, the region is challenging to map for short read NGS technologies due to the repetitive nature and high GC content. At least the five four repeats critical for MODY however are reasonably well covered in srWGS and WES data, and should be callable in routine testing. Although the fifth repeat does have increasing numbers of multimapping reads which may start to reduce sensitivity.; to: Specific CEL gene variants have been associated with MODY8, and potentially hereditary chronic pancreatitis, in 5 families to date (PMID:37726640). All families have single base frame shift deletions in the VNTR (Variable Number of Tandem Repeats) region of the last exon (exon 11) of the CEL gene, specifically in the first (DEL1), fourth and fifth (DEL4,5) repeat of the VNTR region (GRCh38 chr9:133,071,168-133,071,332).

Experimental evidence supports a Gain of Function, dominant negative mechanism of pathogenicity, in which certain frameshift variants cause the resulting protein to from toxic cellular aggregates (29233499). Crucially, an extended number of frameshifted repeats seem to be required to facilitate the formation of these aggregates (27650499, 38483348, 33862081). This is likely due to the increased presence of cysteine residues facilitating di-sulphide bonds, and the decreased presence of Threonine residuce that undergo O-glycosylation which is necessary for protein secretion. In addition, heterozygous NMD variants are common in gnomAD v4 for this gene (pLI = 0, o/e = 0.74), further arguing against dominant LoF as a pathogenic mechanism despite the potential for late onset and reduced penetrance.

Importantly, both more distal frameshift deletions, distal single base insertions (beyond repeat 7), and frameshift variants that result in a premature termination codon in the same repeat, have no strong evidence for pathogenicity to date as they do not result in toxic protein aggregation (38483348, 33862081). Some insertions in the proximal VNTR region, in particular in the first and fourth repeat (INS1, INS4), may confer an increased risk of pancreatitis, but evidence so far remains inconclusive (PMID:38483348). More distal single base insertions (beyond repeat 7) and distal deletions have been described as likely benign.

From a technical perspective, the region is challenging to map for short read NGS technologies due to the repetitive nature and high GC content. At least the five four repeats critical for MODY however are reasonably well covered in srWGS and WES data, and should be callable in routine testing. Although the fifth repeat does have increasing numbers of multimapping reads which may start to reduce sensitivity.
Genomic screening in children: BabyScreen+ v0.92 CEL Seb Lunke changed review comment from: Specific CEL gene variants have been associated with MODY8, and potentially hereditary chronic pancreatitis, in 5 families to date (PMID:37726640). All families have single base frame shift deletions in the VNTR (Variable Number of Tandem Repeats) region of the last exon (exon 11) of the CEL gene, specifically in the first (DEL1), fourth and fifth (DEL4,5) repeat of the VNTR region (GRCh38 chr9:133,071,168-133,071,332).

Experimental evidence supports a Gain of Function, dominant negative mechanism of pathogenicity, in which certain frameshift variants cause the resulting protein to from toxic cellular aggregates (29233499). Crucially, an extended number of frameshifted repeats seem to be required to facilitate the formation of these aggregates (27650499, 38483348, 33862081). This is likely due to the increased presence of cysteine residues facilitating di-sulphide bonds, and the decreased presence of Threonine residuce that undergo O-glycosylation which is necessary for protein secretion.

Importantly, both more distal frameshift deletions, distal single base insertions (beyond repeat 7), and frameshift variants that result in a premature termination codon in the same repeat, have no strong evidence for pathogenicity to date as they do not result in toxic protein aggregation (38483348, 33862081). Some insertions in the proximal VNTR region, in particular in the first and fourth repeat (INS1, INS4), may confer an increased risk of pancreatitis, but evidence so far remains inconclusive (PMID:38483348). More distal single base insertions (beyond repeat 7) and distal deletions have been described as likely benign.

From a technical perspective, the region is challenging to map for short read NGS technologies due to the repetitive nature and high GC content. At least the five four repeats critical for MODY however are reasonably well covered in srWGS and WES data, and should be callable in routine testing. Although the fifth repeat does have increasing numbers of multimapping reads which may start to reduce sensitivity.; to: Specific CEL gene variants have been associated with MODY8, and potentially hereditary chronic pancreatitis, in 5 families to date (PMID:37726640). All families have single base frame shift deletions in the VNTR (Variable Number of Tandem Repeats) region of the last exon (exon 11) of the CEL gene, specifically in the first (DEL1), fourth and fifth (DEL4,5) repeat of the VNTR region (GRCh38 chr9:133,071,168-133,071,332).

Experimental evidence supports a Gain of Function, dominant negative mechanism of pathogenicity, in which certain frameshift variants cause the resulting protein to from toxic cellular aggregates (29233499). Crucially, an extended number of frameshifted repeats seem to be required to facilitate the formation of these aggregates (27650499, 38483348, 33862081). This is likely due to the increased presence of cysteine residues facilitating di-sulphide bonds, and the decreased presence of Threonine residuce that undergo O-glycosylation which is necessary for protein secretion. In addition, heterozygous NMD variants are common in gnomAD v4 for this gene, further arguing against dominant LoF as a pathogenic mechanism despite the potential for late onset and reduced penetrance.

Importantly, both more distal frameshift deletions, distal single base insertions (beyond repeat 7), and frameshift variants that result in a premature termination codon in the same repeat, have no strong evidence for pathogenicity to date as they do not result in toxic protein aggregation (38483348, 33862081). Some insertions in the proximal VNTR region, in particular in the first and fourth repeat (INS1, INS4), may confer an increased risk of pancreatitis, but evidence so far remains inconclusive (PMID:38483348). More distal single base insertions (beyond repeat 7) and distal deletions have been described as likely benign.

From a technical perspective, the region is challenging to map for short read NGS technologies due to the repetitive nature and high GC content. At least the five four repeats critical for MODY however are reasonably well covered in srWGS and WES data, and should be callable in routine testing. Although the fifth repeat does have increasing numbers of multimapping reads which may start to reduce sensitivity.
Genomic screening in children: BabyScreen+ v0.92 CEL Seb Lunke reviewed gene: CEL: Rating: GREEN; Mode of pathogenicity: Other; Publications: 27650499, 29233499, 33862081, 37726640, 38483348; Phenotypes: Maturity-onset diabetes of the young, type VIII, MIM#609812; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic screening in children: BabyScreen+ v0.83 CEL Zornitza Stark Tag treatable tag was added to gene: CEL.
Tag endocrine tag was added to gene: CEL.
Genomic screening in children: BabyScreen+ v0.78 CEL Zornitza Stark Tag for review tag was added to gene: CEL.
Genomic screening in children: BabyScreen+ v0.67 Zornitza Stark Copied gene CEL from panel Maturity-onset Diabetes of the Young
Genomic screening in children: BabyScreen+ v0.67 CEL Zornitza Stark gene: CEL was added
gene: CEL was added to Genomic screening in children: BabyScreen+. Sources: Expert Review Green,Royal Melbourne Hospital
technically challenging tags were added to gene: CEL.
Mode of inheritance for gene: CEL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CEL were set to 24062244; 21784842; 19760265; 18544793; 17989309; 16369531; 29233499; 27650499
Phenotypes for gene: CEL were set to Maturity-onset diabetes of the young, type VIII, 609812
Genomic screening in children: BabyScreen+ v0.59 SMARCAL1 Lilian Rudd gene: SMARCAL1 was added
gene: SMARCAL1 was added to Genomic screening in children: BabyScreen+. Sources: Expert list
Mode of inheritance for gene: SMARCAL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMARCAL1 were set to PMID: 20301550
Phenotypes for gene: SMARCAL1 were set to Schimke immunoosseous dysplasia MIM#242900
Review for gene: SMARCAL1 was set to GREEN
Added comment: Established gene-disease association.

Childhood onset, multi-system disorder

Treatment: haematopoietic stem cells transplantation, renal transplant described.
Sources: Expert list