Mechanisms for nonrecurrent genomic rearrangements associated with CMT1A or HNPP: rare CNVs as a cause for missing heritability.
Genomic rearrangements involving the peripheral myelin protein gene (PMP22) in human chromosome 17p12 are associated with neuropathy: duplications cause Charcot-Marie-Tooth disease type 1A (CMT1A), whereas deletions lead to hereditary neuropathy with liability to pressure palsies (HNPP). Our previous studies showed that >99% of these rearrangements are recurrent and mediated by nonallelic homologous recombination (NAHR). Rare copy number variations (CNVs) generated by nonrecurrent rearrangements also exist in 17p12, but their underlying mechanisms are not well understood. We investigated 21 subjects with rare CNVs associated with CMT1A or HNPP by oligonucleotide-based comparative genomic hybridization microarrays and breakpoint sequence analyses, and we identified 17 unique CNVs, including two genomic deletions, ten genomic duplications, two complex rearrangements, and three small exonic deletions. Each of these CNVs includes either the entire PMP22 gene, or exon(s) only, or ultraconserved potential regulatory sequences upstream of PMP22, further supporting the contention that PMP22 is the critical gene mediating the neuropathy phenotypes associated with 17p12 rearrangements. Breakpoint sequence analysis reveals that, different from the predominant NAHR mechanism in recurrent rearrangement, various molecular mechanisms, including nonhomologous end joining, Alu-Alu-mediated recombination, and replication-based mechanisms (e.g., FoSTeS and/or MMBIR), can generate nonrecurrent 17p12 rearrangements associated with neuropathy. We document a multitude of ways in which gene function can be altered by CNVs. Given the characteristics, including small size, structural complexity, and location outside of coding regions, of selected rare CNVs, their identification remains a challenge for genome analysis. Rare CNVs may potentially represent an important portion of "missing heritability" for human diseases.
Zhang
Feng
F
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Seeman
Pavel
P
Liu
Pengfei
P
Weterman
Marian A J
MA
Gonzaga-Jauregui
Claudia
C
Towne
Charles F
CF
Batish
Sat Dev
SD
De Vriendt
Els
E
De Jonghe
Peter
P
Rautenstrauss
Bernd
B
Krause
Klaus-Henning
KH
Khajavi
Mehrdad
M
Posadka
Jan
J
Vandenberghe
Antoon
A
Palau
Francesc
F
Van Maldergem
Lionel
L
Baas
Frank
F
Timmerman
Vincent
V
Lupski
James R
JR
D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D017353:Gene Deletion; D020440:Gene Duplication; D015417:Hereditary Sensory and Motor Neuropathy; D006801:Humans; D009185:Myelin Proteins / Q000235:genetics*; D010243:Paralysis / Q000235:genetics*; D014178:Translocation, Genetic
D009185:Myelin Proteins; C073687:PMP22 protein, human