Characterisation of two deletions involving NPC1 and flanking genes in Niemann–Pick Type C disease patients

Niemann–Pick type C (NPC) disease is an autosomal recessive lysosomal disorder characterised by the accumulation of a complex pattern of lipids in the lysosomal-late endosomal system. More than 300 disease-causing mutations have been identified so far in the NPC1 and NPC2 genes, including indel, mis...

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Bibliographic Details
Published in:Molecular genetics and metabolism 2012-12, Vol.107 (4), p.716-720
Main Authors: Rodríguez-Pascau, Laura, Toma, Claudio, Macías-Vidal, Judit, Cozar, Mónica, Cormand, Bru, Lykopoulou, Lilia, Coll, Maria Josep, Grinberg, Daniel, Vilageliu, Lluïsa
Format: Article
Language:English
Subjects:
Alleles
Array-CGH
Base Sequence
Carrier Proteins - genetics
Child, Preschool
Exons
Fatal Outcome
Gene deletions
Gene Order
Humans
Infant
Introns
Membrane Glycoproteins - genetics
Niemann-Pick Disease, Type C - diagnosis
Niemann-Pick Disease, Type C - genetics
Niemann–Pick type C
NPC1 gene
Pedigree
QMPSF
Sequence Deletion
SNP analysis
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Summary:Niemann–Pick type C (NPC) disease is an autosomal recessive lysosomal disorder characterised by the accumulation of a complex pattern of lipids in the lysosomal-late endosomal system. More than 300 disease-causing mutations have been identified so far in the NPC1 and NPC2 genes, including indel, missense, nonsense and splicing mutations. Only one genomic deletion, of more than 23kb, has been previously reported. We describe two larger structural variants, encompassing NPC1 and flanking genes, as a cause of the disease. QMPSF, SNP inheritance and CytoScan® HD Array were used to confirm and further characterise the presence of hemizygous deletions in two patients. One of the patients (NPC-57) bore a previously described missense mutation (p.T1066N) and an inherited deletion that included NPC1, C18orf8 and part of ANKRD29 gene. The second patient (NPC-G1) had a 1-bp deletion (c.852delT; p.F284Lfs*26) and a deletion encompassing the promoter region and exons 1–10 of NPC1 and the adjacent ANKRD29 and LAMA3. This study characterised two novel chromosomal microdeletions at 18q11–q12 that cause NPC disease and provide insight into missing NPC1 mutant alleles. ► Deletions including the NPC1 and flanking regions gene as cause of Niemann–Pick C. ► Deletions have been characterised by QMPSF, SNP segregation analysis and array-CGH. ► This information was used for prenatal diagnosis in one of the cases.
ISSN:1096-7192
1096-7206
DOI:10.1016/j.ymgme.2012.10.004