CMT1A/HNPP: rare CNVs as a cause for missing heritability

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Am J Hum Genet. 2010 Jun 11;86(6):892-903. Epub 2010 May 20.

Mechanisms for nonrecurrent genomic rearrangements associated with CMT1A or

HNPP: rare CNVs as a cause for missing heritability.

Zhang F, Seeman P, Liu P, Weterman MA, Gonzaga-Jauregui C, Towne CF, Batish SD,

De Vriendt E, De Jonghe P, Rautenstrauss B, Krause KH, Khajavi M, Posadka J,

Vandenberghe A, Palau F, Van Maldergem L, Baas F, Timmerman V, Lupski JR.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston,

TX 77030, USA.

Abstract

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.