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The Many Faces of CNVs: The Case of 1q21.1

22 December 2008. Earlier this year, back-to-back articles in Nature implicated rare 1q21.1 deletions and duplications in schizophrenia (see SRF related news story), but as illustrated by two new reports that tie deletions and duplications in this same genetic region to a wide array of developmental and behavioral phenotypes, the brave new world of copy number variation (CNV) research is spawning as many questions as answers.

These studies—one published in October in the New England Journal of Medicine from the laboratory of Evan Eichler at the University of Washington (Mefford et al., 2008) and the other in the December issue of Nature Genetics, by Ankita Patel and colleagues at Baylor College of Medicine (Brunetti-Pierri, 2008)—took a different approach. Instead of conducting genomewide searches for CNVs in one disease, both research groups specifically tested for 1q21.1 CNVs in groups of patients who had been referred for genetic testing with widely diverse phenotypes suggesting disruptions in neural development (the 1q21.1 region contains some 27 genes, most expressed in the brain), including mental retardation, autism, and various congenital brain anomalies.

In the earlier study from the International Schizophrenia Consortium (ISC), which compared 3,291 patients with schizophrenia with 3,181 controls, deletions in 1q21.1 were found in 10 cases and one control (ISC; International Schizophrenia Consortium, 2008). The companion work by Stefansson and colleagues identified 66 de novo CNVs in a population-based sample, which were winnowed down in two successive association studies to three CNVs, including recurrent 1q21.1 deletions, warranting further study. Ultimately, 11 of 4,718 cases (0.23 percent) were found to carry 1q21.1 deletions, compared to only eight of 41,999 controls (0.02 percent) (Stefansson et al., 2008). As the intensive discussion at SRF on these papers (see commentary on SRF related news story) and on the earlier CNVs-in-schizophrenia paper by Walsh and colleagues (see commentary on SRF related news story) attest, researchers are divided about the meaning and usefulness of these findings. In particular, the current papers recall the objections of some commentators that these deletions may generally perturb brain development, with psychosis only one of many possible manifestations.

A wide spectrum
In the New England Journal study, first authors Heather Mefford and Andrew Sharp and an international team of collaborators screened 5,218 such patients and identified a recurrent 1.35 mb deletion including at least seven genes in 25 persons (0.5 percent). The deletion was not found in a subsequent screen of 4,737 control subjects. A reciprocal duplication was found in nine patients (0.2 percent), and in only one control subject. Five patients with 1q21.1 CNVs, four with a deletion and one with a duplication, were excluded from the study because they had additional chromosomal abnormalities that could have contributed to their phenotype. Some deletions were de novo, some inherited, and some of unknown origin.

Most patients with deletions had mild to moderate developmental delay (76.2 percent) and dysmorphic features (81 percent), but five had normal cognitive development, and there were four parents of patients who carried the same deletion but were apparently unaffected. As for duplications, seven of the eight carriers had learning problems or mental retardation, and four of the eight had autism or autistic features. However, patients with 1q21.1 CNVs exhibited a range of skeletal, facial, cardiac, ocular, and neurological features with no apparent pattern. “[D]etailed clinical evaluations of affected persons disclosed a much broader spectrum of phenotypes than anticipated, dispelling any notion of syndromic disease,” the team writes. “These results. . .also further dispel the notion that rare copy-number variants will necessarily follow the one gene (or one rearrangement)-one disease model.” (See Q&A with authors Mefford and Eichler below).

A similarly broad spectrum of phenotypes associated with 1q21.1 CNVs is reported in the Nature Genetics study, led by first authors Nicola Brunetti-Pierri and Jonathan Berg. The research group examined 16,557 patient samples with comparative genomic hybridization over the course of four years, assembling what they call “the largest collection of individuals with microdeletions or microduplications in chromosome 1q21.1 reported in the literature”: 27 patients with deletions and 17 with duplications (with detailed clinical information available for 21 and 15 patients, respectively).

However, aside from consistent associations of 1q21.1 deletions with decreased head circumference (which has also been observed in schizophrenia; see, e.g., Ward et al., 1996) and duplications with increased head circumference, the range of observed phenotypes was wide and exhibited no clear syndromic pattern among patients (e.g., short stature, eye abnormalities, hallucinations, seizures, brain malformations with deletions; heart defects, scoliosis, autism, hydrocephalus with duplications). Moreover, like the Mefford and Sharp team, the group reports that 1q21.1 deletions and duplications can be carried by apparently unaffected individuals, prompting them to question “whether 1q21.1 microdeletions and microduplications are benign CNVs or are pathogenic variants with incomplete penetrance.”

In commentary accompanying the Nature Genetics paper, Michael O’Donovan, George Kirov, and Michael Owen (all of whom took part in the ISC genomewide CNV study) assess the methodological dilemma posed by CNVs thus far. “[P]henotype-led approaches have greater power to implicate specific CNVs in specific disorders,” they write, “but they are unlikely to capture the full range of phenotypic diversity. In contrast, the CNV-led approach can expand our knowledge of the range of phenotypes related to a specific CNV, but. . .we cannot be certain which specific phenotypes drive this enrichment.”—Pete Farley.

Brunetti-Pierri N, Berg JS, Scaglia F, Belmont J, Bacino CA, Sahoo T, Lalani SR, Graham B, Lee B, Shinawi M, Shen J, Kang SH, Pursley A, Lotze T, Kennedy G, Lansky-Shafer S, Weaver C, Roeder ER, Grebe TA, Arnold GL, Hutchison T, Reimschisel T, Amato S, Geragthy MT, Innis JW, Obersztyn E, Nowakowska B, Rosengren SS, Bader PI, Grange DK, Naqvi S, Garnica AD, Bernes SM, Fong CT, Summers A, Walters WD, Lupski JR, Stankiewicz P, Cheung SW, Patel A. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet. 2008 Dec;40(12):1466-71. Abstract

Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, Huang S, Maloney VK, Crolla JA, Baralle D, Collins A, Mercer C, Norga K, de Ravel T, Devriendt K, Bongers EM, de Leeuw N, Reardon W, Gimelli S, Bena F, Hennekam RC, Male A, Gaunt L, Clayton-Smith J, Simonic I, Park SM, Mehta SG, Nik-Zainal S, Woods CG, Firth HV, Parkin G, Fichera M, Reitano S, Lo Giudice M, Li KE, Casuga I, Broomer A, Conrad B, Schwerzmann M, Räber L, Gallati S, Striano P, Coppola A, Tolmie JL, Tobias ES, Lilley C, Armengol L, Spysschaert Y, Verloo P, De Coene A, Goossens L, Mortier G, Speleman F, van Binsbergen E, Nelen MR, Hochstenbach R, Poot M, Gallagher L, Gill M, McClellan J, King MC, Regan R, Skinner C, Stevenson RE, Antonarakis SE, Chen C, Estivill X, Menten B, Gimelli G, Gribble S, Schwartz S, Sutcliffe JS, Walsh T, Knight SJ, Sebat J, Romano C, Schwartz CE, Veltman JA, de Vries BB, Vermeesch JR, Barber JC, Willatt L, Tassabehji M, Eichler EE. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med. 2008 Oct 16;359(16):1685-99. Abstract

O’Donovan MC, Kirov G, Owen MJ. Phenotypic variations on the theme of CNVs. Nat Genet. 2008 Dec;40(12):1392-3. Abstract

Q&A with Evan Eichler and Heather Mefford. Questions by Pete Farley.

SRF: What led you to think about this chromosomal region to begin with?
Eichler: This is one of the regions we identified way back in 2002. We developed a duplication map of the human genome after the Genome Project was finished, and we looked for regions that we thought had an architecture, that would predispose to instability. It’s known that duplicated sequences promote genomic instability (this is some work from Lupski and others over the years), and so when we developed this map of duplications, we used it as a kind of morbidity map to predict unstable regions in the human genome. The 1q21 region was one of about 150 regions that we identified back in 2002, and in 2004 we started screening patients with mental retardation for gains and losses of these hotspots in the genome. Andy Sharp in 2006, from my group, published one patient with a 1q21 deletion, based on a small screen of about 300 children with mental retardation. What we did over the last couple of years was just take on each of these regions, from the list of about a dozen regions that we identified in 2006, and target each of those systematically in children with mental retardation and more broadly in children with autism spectrum disorder. Heather at that point picked it up and began screening larger numbers of patients for the 1q21 deletion and working with other groups to really nail down the features of this particular “syndrome.” Ironically, the point of the paper was that, in the end, the deletion eludes syndromic classification.
Mefford: The reason we focused on this was for just that reason; we saw a peppering in the literature of case reports or small series of individuals with different phenotypes who had alterations in this region. And it became very clear that people weren’t sure what to do with that information. So our goal was to really systematically look at both affected individuals and controls to first answer the question, Are alterations in this region pathogenic?
Eichler: I have to tell you, over the last two years, we’ve flip-flopped probably at least three or four times as to whether the deletion event was really disease-causing. Once we started to pick up more and more children with mental retardation with the 1q21 deletion, we started to dig into the phenotypes.

That’s when we got confused because these kids looked very different clinically. They didn’t really have strong dysmorphology. Then we would find parents that were unaffected, and we went back to clinicians and they confirmed that in many cases, about half the cases, the parents carried the event, the deletion event, but were essentially unaffected with respect to what we saw in the kids.

So we went from thinking it's just a rare polymorphism to being a disease, back to being a polymorphism, least two or three times. I think what finally cinched it for us was 1) the work Heather did for us to pull all of these patients together with the other groups where we started to see what I would call sub-phenotypes or sub-syndromes, where we saw kids having some features that were in common. So some would have cardiac defects, some would have cataracts, some would have severe mental retardation with other similarities. And then 2) the screen of more than 5,000 “normal individuals,” and finding this event essentially nonexistent, at least the deletion event, in those cases. So that convinced us that this event was pathogenic, but we knew that this would be problematic for the diagnostic community. It’s not something where you can tell the parent, Well, your child is going to have severe mental retardation, or your child could be normal but might have an increased risk for cardiac defects, or your child could grow up with a normal heart, and become schizophrenic later on in life. The schizophrenia details came from the other papers that were published, not from our group, but from the two papers that were published this summer in Nature.

SRF: Yes, the paper, as your conclusion indicates, raises as many questions as it answers, I guess.
Eichler: I think it’s important that it is actually changing the way we think about it—at least for me; I’m not going to say for all human geneticists—but it’s changing the way I was taught to think about human disease. I was taught to think that you have a lesion, and you have a phenotype, and there’s going to be some variability in that phenotype, but this is actually jumping across different diseases. So the idea is that you can have a schizophrenic, and then you can have a child with cardiac defect, and normal mentation, and then you have a child that is severely handicapped, or an autistic child that has no problem with the heart. These are such wildly diverse clinical manifestations, it makes me start to think that maybe we should be thinking about them just as cases and controls—kids with some neurologic impairment versus ones without. Maybe we should be lumping many different classes of diseases together.

SRF: In a general hypothesis that you put forward about explaining this phenotypic variation, you said that “modifiers” played quite an important role, but you seemed to eliminate the first suspects that anyone would think of: recessive variants, epigenetic effects/imprinting. So where do you think the culprits are?
Eichler: To me, these are all different types of modifiers, so I guess one question would be, Is the modifier going to be located in cis, so in the region of the microdeletion itself, or is it going to be somewhere else in the genome? And I think the most logical place to begin would be in the region itself, right? To look at the genes that are underneath the deletion or the duplication, look for what haplotypes there are there. The other thing to consider, which I think is probably important, are the environmental influences when these conceptuses are formed. There may be different disease courses determined not just by the genetic background, but also by the environmental insults that this embryo or this conceptus is exposed to. I think we’re really quite ignorant about that aspect.
Mefford: In the case of 1q21, we only looked at two obvious genes for two of the phenotypes. One for heart disease and one for cataracts. And the bigger question is why are some of these kids severely mentally retarded and why do some people grow up and have schizophrenia? Although we made an initial attempt of look at some of these things, we really haven’t gotten anywhere with respect to looking globally at modifiers that might affect brain development and cognition.

I agree with Evan. I think that looking in the region is the first place to look, but we can’t forget that there may be SNPs in genes or copy number variants elsewhere in the genome that might also influence what the final phenotype is going to be and what you’ll get in the individual.
Eichler: One way to think about this is that because it’s such a large region, and it takes out so many genes, it creates such a sensitized individual for copy number imbalance, or at least in terms of gene expression. So if you can look at all of the different genes, and different processes they played in that critical region, you can imagine that any other mutation that occurs somewhere else, that in a normal individual would not have a huge effect, now in fact manifests itself and can have a very significant effect in terms of what the outcome is in the child. Obviously, targeting these regions and resequencing is important, and we and the other groups want to find the genes that are responsible for the different aspects of the phenotype. But I think the most important thing that we need right now is to combine sample collections with detailed clinical information. When we start looking at large numbers it’s not as confusing I think as the first blush of analysis. We start to see certain groups of patients grouped together and, say, these ones all have microcephaly, all these kids have heart defects, all these kids have cataracts.

So if we combine ours, Jim Lupski’s collection, and other collections that are being made across the world, we could in principle have a detailed dissection of the phenotype that would help find the genes that are responsible for different aspects. Down the road, we might be able to predict the outcome of some of the kids with the 1q21 deletion much better.

SRF: Just curiosity on my part, but you seem to use terminology other than CNV in the paper: things like unbalanced micro-rearrangements. Is that just a preference of nomenclature or is there some theoretical thing embedded in that?
Eichler: Actually, that stems from complaints from the cytogenetics community. There are well-established professors in cytogenetics that have criticized the use of CNV to refer to something that is pathogenic. And that’s because implied in copy number variant, at least until probably last year, was the idea that variant equals benign. Microdeletion and microduplication to cytogeneticists typically means that you have something pathogenic, but there was actually a move among a few cytogeneticists to write a white paper or a piece that would help clarify this. But I would have to say that in the last year there’s been so much interchange between the use of CNV and microdeletion and microduplication, I think it’s a foregone conclusion now that it's almost impossible to stem that tide and change the usage back to the way that cytogeneticists viewed it originally.

SRF: And one last question: your lab’s output is prolific and very diverse in terms of the sorts of questions you’re looking at including a lot of things like the platypus paper, which had an evolutionary or phylogenetic focus. The new paper in Science on 17q21, and this other paper that came out recently, by Brunetti-Pierri, on 1q21—they all touch on evolutionary questions, and I’m curious about whether you think evolutionary and clinical questions, in genomics in particular, will continue to be intertwined and what those two perspectives can bring to bear on one another.
Eichler: This has been the mission of my lab for probably 10 years. We see clinical mutations and evolutionary process as all the same, and we find that both inform upon each other. The clinical information is really valuable because it gives us real-time information on mutations in humans. The evolutionary process tells things about the mechanism and the patterns that we can use. If you think about the way that we strategized and went after these regions to begin with, it’s largely from an evolutionary perspective: finding things that were CNVs five to 10 million years ago, and using them to predict locations of new CNV’s that cause disease. So our approach has always been intertwined with evolution and disease, and I think it’s a very powerful way to go. In the future, this approach will be commonplace. I think it’s unfortunate that a lot of human geneticists do not have a strong background in or consider evolutionary biology, because I think that would give them more insights than they currently have. It’s like history is bound to repeat itself, as we say, and the genome tells us the same thing over and over again. Instability that we’ve seen happen 10 million years ago occurred in the same regions that are unstable in us now, and for good reason. I guess our twist on it, which is probably different from most other labs, is that we’re interested in finding the flip side or positive aspects of duplication architecture. We know that duplications cause disease, and we know that humans are enriched for these duplications, and we have lots of them that are interspersed. This creates long-term hotspots of instability like a series of volcanoes in our genome that are going to erupt at any moment. The question is, Why is that architecture there at all? What we have been finding, and publishing from our evolutionary analyses, is that embedded in these duplicated regions are new genes and gene families that seem to have evolved specifically in the human and great ape lineage. And so we’re very interested in these, because we think they’re going to tell us something fundamental about the evolution of our species, at the same time predicting sites of instability that cause disease.

SRF: Any parting thoughts?
Eichler: I know this is a phrase that has been used way too much in this field, but I believe this is the tip of the iceberg. I think that the way that we’ve been thinking about the common disease-common variant hypothesis has been, in part, shadowplay. Many of the substantive variants—those with high odds ratios—are coming from rare variants. The rare variant-common disease hypothesis is now gaining more and more traction. The idea that we now can explain maybe as much as 15 percent of mental retardation, autism, and other complex neurologic phenotypes by this model is the really important message. This message should reverberate to other communities that are studying other complex diseases, such as asthma, diabetes, or hypertension. I would be surprised if this model isn’t going to be important for those complex diseases as well. It will be interesting to see what the next couple of years will hold, but I would predict even more papers on more diverse phenotypes related to large copy number variants. I think what is really cool about this whole field, if you will, is that we have so much instability in our genome, and yet as a species we’re so successful. And we have a huge diversity of diseases that will be essentially evolutionarily very, very young. We’re talking about diseases that are going to be specific to specific families, a few generations old, as opposed to this idea that diseases are inherited from mutations that happened hundreds if not thousands of generations ago in populations that left Africa. So I think human disease studies and human genomics and human evolutionary work really is a personal issue, and I think it’s really the fun part. I’m still wrapping my head around the idea that we have so much variation in our genome and some of us are even going to be different from either of our parents. We’re not just the sum of both of them; we have more or less material than our parents for some small number of loci. It’s kind of a radical concept. If you had asked me even eight years ago, I would have thought the genome was kind of a sacrosanct thing. You can’t mess with it too much—small mutations, yes, but big mutations, probably not likely, not over a long haul. But our genome is really quite plastic. It’s amazing that any of us are normal at all, and maybe like I said before, none of us really are. And so that’s kind of the beauty of it.

SRF: That’s comforting in a way.
Eichler: It is. I was thinking, if I had to write a book, the title of it would be “No Perfect Genome.” Because there is no individual out there who has a perfect genome in terms of mutation, in terms of organization or structure. So we’re all screwed up a little bit, and maybe that’s why we’re human.
Mefford: I’m not sure I can top that. But one of my thoughts from a more clinical perspective is I think the nice thing about the type of study we did is we brought together a large number of groups and a large number of patients and controls. I think we picked all the low hanging fruit for some of these disorders and the obvious pathogenic events, and we’re going to see more and more cases like the 1q21 rearrangements where it’s not quite clear if there’s one phenotype or more. Really bringing together large groups of people and patients and genotypes is going to be required to understand the real phenotypic diversity and pathogenicity of some of the rearrangements. I think human genetics is going to be more and more collaborative research and large numbers are going to be important. It’s going to be important to help people on the clinical side also to be able to talk to their patients and their families about what all these findings mean, because we’re continuing to perform our ACGH and sometimes it’s not clear what it means. It’s going to take a lot of work to be able to explain that.

SRF: Yes, I thought that was quite an interesting part of the paper, about the practical ramifications for genetic counseling.
Eichler: I have talked to clinicians in diagnostic centers, and I have to say that they’re probably as flummoxed as we are, probably more so, because they have to convey this information to families and Heather actually does quite a bit of that herself. We’ve been getting quite a few e-mails from families asking us what does this mean for them and their kids.

And I have to tell you that this is quite a sobering thing because you know in many ways, not to trivialize it, but all we can tell them is there’s really a good chance that their kid is going to be sick. It doesn't really give them a lot of news. When they realize that their father, for example, carries the same deletion and is normal, how do you make a decision on the child or how do you make a decision on how to raise that child? If children are born and are normal, do you need to have someone watch them for the rest of their lives to see if they develop schizophrenia. These are really big questions that affect people in very significant ways. That aspect of it is supposed to be worrying, but also we have to be very careful in what we say and what we don’t say.

SRF: Well, I thank you very much, both of you, for your time, and thanks for the interesting paper, also.

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