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Discovery and characterization of 17q12 deletions as high-risk variants for neurodevelopmental conditions

Discovery and characterization of 17q12 deletions as high-risk variants for neurodevelopmental conditions. During my postdoctoral training in neurogenetics at Emory University, we identified a rare deletion in chromosome 17q12 among people referred for clinical genetic testing because of autism. As a part of an international collaboration, we expanded our studies to several other populations and discovered that this copy number variant (CNV) also increased risk for schizophrenia. As a follow up to these studies, we wrote the GeneReviews chapter on 17q12 deletions, serving as a guide for clinicians and researchers focusing on this area.

December 8, 2016


17q12 Recurrent Deletion Syndrome

Marissa W Mitchel, Daniel Moreno-De-Luca, Scott M Myers, Rebecca V Levy, Stefanie Turner, David H Ledbetter, Christa L Martin, Margaret P Adam, Holly H Ardinger, Roberta A Pagon, Stephanie E Wallace, Lora JH Bean, Karen W Gripp, Ghayda M Mirzaa, Anne Amemiya

The 17q12 recurrent deletion syndrome is characterized by variable combinations of the three following findings: structural or functional abnormalities of the kidney and urinary tract, maturity-onset diabetes of the young type 5 (MODY5), and neurodevelopmental or neuropsychiatric disorders (e.g., developmental delay, intellectual disability, autism spectrum disorder, schizophrenia, anxiety, and bipolar disorder). Using a method of data analysis that avoids ascertainment bias, the authors determined that multicystic kidneys and other structural and functional kidney anomalies occur in 85% to 90% of affected individuals, MODY5 in approximately 40%, and some degree of developmental delay or learning disability in approximately 50%. MODY5 is most often diagnosed before age 25 years (range: age 10-50 years).

November 12, 2010

Am J Hum Genet

Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia

Moreno-De-Luca D; SGENE Consortium, Mulle JG; Simons Simplex Collection Genetics Consortium, Kaminsky EB, Sanders SJ; GeneSTAR, Myers SM, Adam MP, Pakula AT, Eisenhauer NJ, Uhas K, Weik L, Guy L, Care ME, Morel CF, Boni C, Salbert BA, Chandrareddy A, Demmer LA, Chow EW, Surti U, Aradhya S, Pickering DL, Golden DM, Sanger WG, Aston E, Brothman AR, Gliem TJ, Thorland EC, Ackley T, Iyer R, Huang S, Barber JC, Crolla JA, Warren ST, Martin CL, Ledbetter DH

Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10⁻⁵). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only.


Rare genetic mutations in autism and other psychiatric conditions

During my master’s training at the Université Pierre et Marie Curie – Sorbonne Universités in Paris, France, we focused on identifying recurrent CNVs at chromosome 15q11.2-q13 and chromosome 22q11.2 in autism and other neurodevelopmental conditions. I expanded on this work during my postdoctoral fellowship in neurogenetics, where I had the opportunity of participating in two international collaborations: the Simons Simplex Collection and the Psychiatric Genomics Consortium. Through these, we identified multiple rare and common variants conferring risk for autism, schizophrenia, and other developmental conditions.  

Sep 23, 2015


Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci

Sanders SJ, He X, Willsey AJ, Ercan-Sencicek AG, Samocha KE, Cicek AE, Murtha MT, Bal VH, Bishop SL, Dong S, Goldberg AP, Jinlu C, Keaney JF 3rd, Klei L, Mandell JD,Moreno-De-Luca D, Poultney CS, Robinson EB, Smith L, Solli-Nowlan T, Su MY, Teran NA, Walker MF, Werling DM, Beaudet AL, Cantor RM, Fombonne E, Geschwind DH, Grice DE, Lord C, Lowe JK, Mane SM, Martin DM, Morrow EM, Talkowski ME, Sutcliffe JS, Walsh CA, Yu TW; Autism Sequencing Consortium, Ledbetter DH, Martin CL, Cook EH, Buxbaum JD, Daly MJ, Devlin B, Roeder K, State MW.

Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).

Feb 1, 2015

JAMA Psychiatry

The role of parental cognitive, behavioral, and motor profiles in clinical variability in individuals with chromosome 16p11.2 deletions.

Moreno-De-Luca A, Evans DW, Boomer KB, Hanson E, Bernier R, Goin-Kochel RP, Myers SM, Challman TD, Moreno-De-Luca D, Slane MM, Hare AE, Chung WK, Spiro JE, Faucett WA, Martin CL, Ledbetter DH.

Importance Most disorders caused by copy number variants (CNVs) display significant clinical variability, often referred to as incomplete penetrance and variable expressivity. Genetic and environmental sources of this variability are not well understood.

Objectives To investigate the contributors to phenotypic variability in probands with CNVs involving the same genomic region; to measure the effect size for de novo mutation events; and to explore the contribution of familial background to resulting cognitive, behavioral, and motor performance outcomes in probands with de novo CNVs.

Jul 22, 2014

Genetic Medicine Reports

Cross-Disorder Comparison of Four Neuropsychiatric CNV Loci

Moreno-De-Luca D, Moreno-De-Luca A, Cubells JF, Sanders SJ

Copy number variants (CNVs) have been identified as a major risk factor in neuropsychiatric disorders. In this review, we describe the phenotypes and syndromic features associated with CNVs at four of the best-characterized risk loci for these disorders: 15q11.2-13.1, 22q11.2, 16p11.2, and 7q11.23. By considering the reported prevalence of these CNVs in autism, intellectual disability, schizophrenia, and controls, we demonstrate a pattern of asymmetric shared risk in which CNVs increase the risk of multiple disorders but to differing degrees. This asymmetric risk sharing is incompatible with a model in which CNVs observed in autism or schizophrenia are secondary to a reduction in IQ, but favors a more complex relationship between individual CNVs and specific neuropsychiatric phenotypes. Finally, we discuss how the lessons learned from CNVs in neuropsychiatric disorders will translate to the expanding list of genes being associated with these disorders through exome sequencing.

May 12, 2014

Autism Research, vol. 7

Modest impact on risk for autism spectrum disorder of rare copy number variants at 15q11.2, specifically breakpoints 1 to 2

Chaste P, Sanders SJ, Mohan KN, Klei L, Song Y, Murtha MT, Hus V, Lowe JK, Willsey AJ, Moreno-De-Luca D, Yu TW, Fombonne E, Geschwind D, Grice DE, Ledbetter DH, Lord C, Mane SM, Martin DM, Morrow EM, Walsh CA, Sutcliffe JS, State MW, Martin CL, Devlin B, Beaudet AL, Cook EH Jr, Kim SJ.

The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1-BP2 CNVs and autism accumulates, the magnitude of the effect of BP1-BP2 CNVs remains elusive, posing a great challenge to recurrence-risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1-BP2 CNVs for ASD as well as their effects on ASD-related phenotypes in a well-characterized ASD sample (n = 2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1-BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD-related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1-BP2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1-BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status. Autism Res 2014, 7: 355–362. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.

Oct 18, 2013

Molecular Psychiatry

Using large clinical data sets to infer pathogenicity for rare copy number variants in autism cohorts.

Moreno-De-Luca D, Sanders SJ, Willsey AJ, Mulle JG, Lowe JK, Geschwind DH, State MW, Martin CL, Ledbetter DH

Copy number variants (CNVs) have a major role in the etiology of autism spectrum disorders (ASD), and several of these have reached statistical significance in case–control analyses. Nevertheless, current ASD cohorts are not large enough to detect very rare CNVs that may be causative or contributory (that is, risk alleles). Here, we use a tiered approach, in which clinically significant CNVs are first identified in large clinical cohorts of neurodevelopmental disorders (including but not specific to ASD), after which these CNVs are then systematically identified within well-characterized ASD cohorts. We focused our initial analysis on 48 recurrent CNVs (segmental duplication-mediated ‘hotspots’) from 24 loci in 31 516 published clinical cases with neurodevelopmental disorders and 13 696 published controls, which yielded a total of 19 deletion CNVs and 11 duplication CNVs that reached statistical significance. We then investigated the overlap of these 30 CNVs in a combined sample of 3955 well-characterized ASD cases from three published studies. We identified 73 deleterious recurrent CNVs, including 36 deletions from 11 loci and 37 duplications from seven loci, for a frequency of 1 in 54; had we considered the ASD cohorts alone, only 58 CNVs from eight loci (24 deletions from three loci and 34 duplications from five loci) would have reached statistical significance. In conclusion, until there are sufficiently large ASD research cohorts with enough power to detect very rare causative or contributory CNVs, data from larger clinical cohorts can be used to infer the likely clinical significance of CNVs in ASD.

Jun 9, 2011


Multiple recurrent de novo copy number variations (CNVs), including duplications of the 7q11.23 Williams-Beuren syndrome region, are strongly associated with autism

Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, Chu SH, Moreau MP, Gupta AR, Thomson SA, Mason CE, Bilguvar K, Celestino-Soper PB, Choi M, Crawford EL, Davis L, Wright NR, Dhodapkar RM, DiCola M, DiLullo NM, Fernandez TV, Fielding-Singh V, Fishman DO, Frahm S, Garagaloyan R, Goh GS, Kammela S, Klei L, Lowe JK, Lund SC, McGrew AD, Meyer KA, Moffat WJ, Murdoch JD, O'Roak BJ, Ober GT, Pottenger RS, Raubeson MJ, Song Y, Wang Q, Yaspan BL, Yu TW, Yurkiewicz IR, Beaudet AL, Cantor RM, Curland M, Grice DE, Günel M, Lifton RP, Mane SM, Martin DM, Shaw CA, Sheldon M, Tischfield JA, Walsh CA, Morrow EM, Ledbetter DH, Fombonne E, Lord C, Martin CL, Brooks AI, Sutcliffe JS, Cook EH Jr, Geschwind D, Roeder K, Devlin B, State MW

We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6–12.0, p = 2.4 × 10-7). We estimate there are 130–234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1.

Jun 21, 2010

BMC Medical Genetics, vol. 11

Search for copy number variants in chromosomes 15q11-q13 and 22q11.2 in obsessive compulsive disorder.

Delorme R, Moreno-De-Luca D, Gennetier A, Maier W, Chaste P, Mössner R, Grabe HJ, Ruhrmann S, Falkai P, Mouren MC, Leboyer M, Wagner M, Betancur C

Obsessive-compulsive disorder (OCD) is a clinically and etiologically heterogeneous syndrome. The high frequency of obsessive-compulsive symptoms reported in subjects with the 22q11.2 deletion syndrome (DiGeorge/velocardiofacial syndrome) or Prader-Willi syndrome (15q11-13 deletion of the paternally derived chromosome), suggests that gene dosage effects in these chromosomal regions could increase risk for OCD. Therefore, the aim of this study was to search for microrearrangements in these two regions in OCD patients.

Mar 12, 2009

Biological Psychiatry

Screening for genomic rearrangements and methylation abnormalities of the 15q11-q13 region in autism spectrum disorders.

Delorme R, Moreno-De-Luca D, Gennetier A, Maier W, Chaste P, Mössner R, Grabe HJ, Ruhrmann S, Falkai P, Mouren MC, Leboyer M, Wagner M, Betancur C.

Maternally derived duplications of the 15q11-q13 region are the most frequently reported chromosomal aberrations in autism spectrum disorders (ASD). Prader-Willi and Angelman syndromes, caused by 15q11-q13 deletions or abnormal methylation of imprinted genes, are also associated with ASD. However, the prevalence of these disorders in ASD is unknown. The aim of this study was to assess the frequency of 15q11-q13 rearrangements in a large sample of patients ascertained for ASD.

Precision medicine for autism and neurodevelopmental conditions

During my training in psychiatry at Yale and in Child and Adolescent Psychiatry at Brown, and now as an Assistant Professor at Brown, I have been focusing on assessing barriers and opportunities for the implementation and dissemination of genetic testing at a large scale within a healthcare system, and on developing and implementing systematic, evidence-based approaches to using genetic information in clinical care for psychiatric conditions that have a high heritability. This translational research work is synergistic with my current clinical activities, which include the establishment of the Genetic Psychiatry Consultation Service within the Verrecchia clinic for Children with Autism and Developmental Disabilities at Bradley Hospital, where we aim to provide  actionable clinical recommendations based on pathogenic genetic results for people with autism or other developmental or neuropsychiatric conditions. 

Apr 1, 2019


Forging the path for PRecISion Medicine in Autism: The PRISMA Neurogenetic Psychiatry Consultation Service

Moreno-De-Luca D.

Psychiatry is at a pivotal stage; advances in neuroscience and genetics are allowing us to understand more clearly how specific changes in neurodevelopment and genetic architecture are contributing to increased risk for several mental health disorders. Nowhere has progress been clearer than in autism spectrum disorders (ASDs), one of the psychiatric conditions with the highest genetic burden, as evidenced by their high heritability. Rare variants, which by definition occur in less than 1% of the population, have a large impact on the etiology of autism, as together they can explain up to 30% of cases of autism. These include highly penetrant copy number variants (CNVs), defined as losses or gains of genetic material, and single nucleotide variants (SNVs), characterized by changes in single base pairs. Because of the increased risk these rare variants confer, many professional societies, including the American Society of Human Genetics and the American College of Medical Genetics and Genomics jointly, the American Academy of Child and Adolescent Psychiatry, and others have recommended genetic testing as the standard of care or a key step in the workup of cases of ASDs. However, the adoption of these recommendations in psychiatry clinics has been quite low. In fact, only close to 5% of patients receive these tests in our population (submitted), which means that the overwhelming majority of people with ASDs are not benefiting from genetically informed health care

Jun 15, 2018

Biological Psychiatry

Found in Translation: Autism Genetics and the Quest for Its Rosetta Stone.

Goldstein J, Ross DA, Moreno De Luca D.

So begins the seminal paper by child psychiatrist Leo Kanner in which he described 11 children who, despite individual differences, displayed a common “inability to relate themselves in the ordinary way to people and situations.” Kanner believed they had “a unique ‘syndrome’, not heretofore reported, which seems to be rare enough” that he called “early infantile autism.” In many respects, his description (“autistic aloneness” and “insistence on sameness”) seems remarkably contemporary. Yet while the phenomenology was accurate, our understanding of almost every other aspect of the condition has evolved considerably.

Feb 2, 2018

Biological Psychiatry

Leveraging the Power of Genetics to Bring Precision Medicine to Psychiatry: Too Little of a Good Thing?

Moreno-De-Luca D, Ross ME, Ross DA.

Imagine, in 1968, a 56-year-old woman presenting to her primary care physician with a progressively worsening cough. Unrelatedly (in her mind)—and ominously (in her physician’s)—she also reports a dull ache in her left hip. Over the next week, a detailed diagnostic evaluation reveals a large mass in her lungs and multiple bone metastases. She is both terrified and embarrassed when her physician first uses the “c word.” She is treated for her cancer with state-of-the art cyclophosphamide chemotherapy, whose adverse effects include unremitting nausea and vomiting and her hair falling out. Sadly, the treatment fails to alter the natural course of her illness and she dies approximately 6 months later.

Jun 18, 2017

Nature Reviews Genetics

Autism genetics: opportunities and challenges for clinical translation

Vorstman JA, Parr JR, Moreno-De-Luca D, Anney RJ, Nurnberger JI Jr, Hallmayer JF.

So begins the seminal paper by child psychiatrist Leo Kanner in which he described 11 children who, despite individual differences, displayed a common “inability to relate themselves in the ordinary way to people and situations.” Kanner believed they had “a unique ‘syndrome’, not heretofore reported, which seems to be rare enough” that he called “early infantile autism.” In many respects, his description (“autistic aloneness” and “insistence on sameness”) seems remarkably contemporary. Yet while the phenomenology was accurate, our understanding of almost every other aspect of the condition has evolved considerably.

Jul 15, 2016

Biological Psychiatry

Beyond the Diagnosis: A Path Toward Understanding Behavior Through the Lens of Rare Genetics

Moreno-De-Luca D.

This is an exciting time for psychiatry. We have long known that many of the disorders we treat, such as autism and schizophrenia, have a strong genetic component, as evidenced by their high heritability, and progress in the past several years has begun to shed light on the specific genetic underpinnings of these conditions. Insights have come from common and rare genetics alike, exemplified by polygenic risk scores, copy number variants (CNVs), and single nucleotide variants (SNVs). With these discoveries, an interesting phenomenon reflecting simultaneously the clinical heterogeneity and overlap of these conditions has continued to emerge—all for one, and one for all: multiple different genetic variants increase risk for the same psychiatric condition, and, conversely, a given genetic variant has been associated with multiple psychiatric diagnoses ( 1 ). Reconciling these numerous streams of genetic evidence poses a challenge that can be tackled in various ways. Although considerable focus has been placed on reducing the clinical heterogeneity by studying discrete isolated psychiatric diagnoses to better understand their underlying biology, a different genotype-first approach ( 2 ) focusing instead on reducing the genetic heterogeneity to elucidate the clinical and behavioral consequences of specific genetic risk factors has likewise proven to be a successful route. This has provided us the opportunity to identify at-risk individuals early in their development, understand the consequences of these genetic changes over time, and understand their relationship with different psychiatric disorders.

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