TY - JOUR
T1 - “Missing mutations” in MPS I: Identification of two novel copy number variations by an IDUA-specific in house MLPA assay
AU - Jahic, Amir
AU - Günther, Sven
AU - Muschol, Nicole
AU - Fossøy Stadheim, Barbro
AU - Braaten, Øivind
AU - Kjensli Hyldebrandt, Hanne
AU - Kuiper, G. -Ann
AU - Tylee, Karen
AU - Wijburg, Frits A.
AU - Beetz, Christian
PY - 2019
Y1 - 2019
N2 - Background: Mucopolysaccharidosis type I (MPS I) is a rare, recessively inherited lysosomal storage disorder, characterized by progressive multi-systemic disease. It is caused by a reduced or absent alpha-l iduronidase (IDUA) enzyme activity secondary to biallelic loss-of-function variants in the IDUA. Over 200 causative variants in IDUA have been identified. Nevertheless, there is a fraction of MPS I patients with only a single mutated IDUA allele detectable. Methods: As genetic testing of MPS I is usually based on sequencing methods, copy number variations (CNVs) in IDUA can be missed and therefore presumably remain underdiagnosed. The aim of this study was the detection of CNVs using an IDUA-specific in house multiplex ligation-dependent probe amplification (MLPA) assay. Results: A total of five unrelated MPS I patient samples were re-analyzed after only a single heterozygous IDUA mutation c.979G>C (p.A327P), c.1469T>C (p.L490P), c.1598C>G (p.P533R), c.1205G>A (p.W402X), c.973-7C>G (p.?) could be identified. We detected a novel splice site variant c.973-7C>G (p.?), as well as two novel CNVs, a large deletion of IDUA exon 14 and 3’UTR c.(1828 + 1_1829-1)_(*1963_?)del, and a large duplication extending from IDUA exon 2 to intron 12 c.(157 + 1_158-1)_(1727 + 1_1728-1)dup. Conclusion: Together with the CNVs we previously identified, a total of four pathogenic IDUA CNVs have now been reported.
AB - Background: Mucopolysaccharidosis type I (MPS I) is a rare, recessively inherited lysosomal storage disorder, characterized by progressive multi-systemic disease. It is caused by a reduced or absent alpha-l iduronidase (IDUA) enzyme activity secondary to biallelic loss-of-function variants in the IDUA. Over 200 causative variants in IDUA have been identified. Nevertheless, there is a fraction of MPS I patients with only a single mutated IDUA allele detectable. Methods: As genetic testing of MPS I is usually based on sequencing methods, copy number variations (CNVs) in IDUA can be missed and therefore presumably remain underdiagnosed. The aim of this study was the detection of CNVs using an IDUA-specific in house multiplex ligation-dependent probe amplification (MLPA) assay. Results: A total of five unrelated MPS I patient samples were re-analyzed after only a single heterozygous IDUA mutation c.979G>C (p.A327P), c.1469T>C (p.L490P), c.1598C>G (p.P533R), c.1205G>A (p.W402X), c.973-7C>G (p.?) could be identified. We detected a novel splice site variant c.973-7C>G (p.?), as well as two novel CNVs, a large deletion of IDUA exon 14 and 3’UTR c.(1828 + 1_1829-1)_(*1963_?)del, and a large duplication extending from IDUA exon 2 to intron 12 c.(157 + 1_158-1)_(1727 + 1_1728-1)dup. Conclusion: Together with the CNVs we previously identified, a total of four pathogenic IDUA CNVs have now been reported.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85071900052&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31319022
U2 - https://doi.org/10.1002/mgg3.615
DO - https://doi.org/10.1002/mgg3.615
M3 - Article
C2 - 31319022
SN - 2324-9269
VL - 7
JO - Molecular genetics and genomic medicine
JF - Molecular genetics and genomic medicine
IS - 9
M1 - e00615
ER -