The Prevalence and Molecular Landscape of Lynch Syndrome in the Affected and General Population.

BACKGROUND: Lynch syndrome (LS) is the most frequent genetically pre-disposed colorectal cancer (CRC) syndrome, accounting for 2-3% of all CRC cases. In Estonia, ~1000 new cases are diagnosed each year. This retroactive and prospective study aimed to estimate the prevalence of LS and describe disease-causing variants in mismatch repair (MMR) genes in a diagnostic setting and in the Estonian general population. METHODS: LS data for the diagnostic cohort were gathered from 2012 to 2022 and data for the general population were acquired from the Estonian Biobank (EstBB). Furthermore, we conducted a pilot study to estimate the improvement of LS diagnostic yield by raising the age limit to >50 years for immunohistochemistry analysis of MMR genes. RESULTS: We estimated LS live birth prevalence between 1930 and 2003 in Estonia at 1:8638 (95% CI: 1: 9859-7588). During the study period, we gathered 181 LS individuals. We saw almost a six-fold increase in case prevalence, probably deriving from better health awareness, improved diagnostic possibilities and the implementation of MMR IHC testing in a broader age group. CONCLUSION: The most common genes affected in the diagnostic and EstBB cohorts were MLH1 and PMS2 genes, respectively. The LS diagnosis mean age was 44.8 years for index cases and 36.8 years (p = 0.003) for family members. In the MMR IHC pilot study, 29% had LS.

Overlap of Genetic Loci for Central Serous Chorioretinopathy With Age-Related Macular Degeneration.

Importance: Central serous chorioretinopathy (CSC) is a serous maculopathy of unknown etiology. Two of 3 previously reported CSC genetic risk loci are also associated with AMD. Improved understanding of CSC genetics may broaden our understanding of this genetic overlap and unveil mechanisms in both diseases. Objective: To identify novel genetic risk factors for CSC and compare genetic risk factors for CSC and AMD. Design, Setting, and Participants: Using International Classification of Diseases, Ninth (ICD-9) and Tenth (ICD-10) Revision code-based inclusion and exclusion criteria, patients with CSC and controls were identified in both the FinnGen study and the Estonian Biobank (EstBB). Also included in a meta-analysis were previously reported patients with chronic CSC and controls. Data were analyzed from March 1 to September 31, 2022. Main Outcomes and Measures: Genome-wide association studies (GWASs) were performed in the biobank-based cohorts followed by a meta-analysis of all cohorts. The expression of genes prioritized by the polygenic priority score and nearest-gene methods were assessed in cultured choroidal endothelial cells and public ocular single-cell RNA sequencing data sets. The predictive utility of polygenic scores (PGSs) for CSC and AMD were evaluated in the FinnGen study. Results: A total of 1176 patients with CSC and 526 787 controls (312 162 female [59.3%]) were included in this analysis: 552 patients with CSC and 343 461 controls were identified in the FinnGen study, 103 patients with CSC and 178 573 controls were identified in the EstBB, and 521 patients with chronic CSC and 3577 controls were included in a meta-analysis. Two previously reported CSC risk loci were replicated (near CFH and GATA5) and 3 novel loci were identified (near CD34/46, NOTCH4, and PREX1). The CFH and NOTCH4 loci were associated with AMD but in the opposite direction. Prioritized genes showed increased expression in cultured choroidal endothelial cells compared with other genes in the loci (median [IQR] of log 2 [counts per million], 7.3 [0.6] vs 4.7 [3.7]; P = .004) and were differentially expressed in choroidal vascular endothelial cells in single-cell RNA sequencing data (mean [SD] fold change, 2.05 [0.38] compared with other cell types; P < 7.1 × 10-20). A PGS for AMD was predictive of reduced CSC risk (odds ratio, 0.76; 95% CI, 0.70-0.83 per +1 SD in AMD-PGS; P = 7.4 × 10-10). This association may have been mediated by loci containing complement genes. Conclusions and Relevance: In this 3-cohort genetic association study, 5 genetic risk loci for CSC were identified, highlighting a likely role for genes involved in choroidal vascular function and complement regulation. Results suggest that polygenic AMD risk was associated with reduced risk of CSC and that this genetic overlap was largely due to loci containing complement genes.

The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions.

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.

Lessons learned during the process of reporting individual genomic results to participants of a population-based biobank.

The return of individual genomic results (ROR) to research participants is still in its early phase, and insight on how individuals respond to ROR is scarce. Studies contributing to the evidence base for best practices are crucial before these can be established. Here, we describe a ROR procedure conducted at a population-based biobank, followed by surveying the responses of almost 3000 participants to a range of results, and discuss lessons learned from the process, with the aim of facilitating large-scale expansion. Overall, participants perceived the information that they received with counseling as valuable, even when the reporting of high risks initially caused worry. The face-to-face delivery of results limited the number of participants who received results. Although the participants highly valued this type of communication, additional means of communication need to be considered to improve the feasibility of large-scale ROR. The feedback collected sheds light on the value judgements of the participants and on potential responses to the receipt of genetic risk information. Biobanks in other countries are planning or conducting similar projects, and the sharing of lessons learned may provide valuable insight and aid such endeavors.

Precise, Genotype-First Breast Cancer Prevention: Experience With Transferring Monogenic Findings From a Population Biobank to the Clinical Setting.

Although hereditary breast cancer screening and management are well accepted and established in clinical settings, these efforts result in the detection of only a fraction of genetic predisposition at the population level. Here, we describe our experience from a national pilot study (2018-2021) in which 180 female participants of Estonian biobank (of >150,000 participants in total) were re-contacted to discuss personalized clinical prevention measures based on their genetic predisposition defined by 11 breast cancer-related genes. Our results show that genetic risk variants are relatively common in the average-risk Estonian population. Seventy-five percent of breast cancer cases in at-risk subjects occurred before the age of 50 years. Only one-third of subjects would have been eligible for clinical screening according to the current criteria. The participants perceived the receipt of genetic risk information as valuable. Fluent cooperation of project teams supported by state-of-art data management, quality control, and secure transfer can enable the integration of research results to everyday medical practice in a highly efficient, timely, and well-accepted manner. The positive experience in this genotype-first breast cancer study confirms the value of using existing basic genomic data from population biobanks for precise prevention.

A cross-disorder dosage sensitivity map of the human genome.

Rare copy-number variants (rCNVs) include deletions and duplications that occur infrequently in the global human population and can confer substantial risk for disease. In this study, we aimed to quantify the properties of haploinsufficiency (i.e., deletion intolerance) and triplosensitivity (i.e., duplication intolerance) throughout the human genome. We harmonized and meta-analyzed rCNVs from nearly one million individuals to construct a genome-wide catalog of dosage sensitivity across 54 disorders, which defined 163 dosage sensitive segments associated with at least one disorder. These segments were typically gene dense and often harbored dominant dosage sensitive driver genes, which we were able to prioritize using statistical fine-mapping. Finally, we designed an ensemble machine-learning model to predict probabilities of dosage sensitivity (pHaplo & pTriplo) for all autosomal genes, which identified 2,987 haploinsufficient and 1,559 triplosensitive genes, including 648 that were uniquely triplosensitive. This dosage sensitivity resource will provide broad utility for human disease research and clinical genetics.

Do Biobank Recall Studies Matter? Long-Term Follow-Up of Research Participants With Familial Hypercholesterolemia.

Recall-by-genotype (RbG) studies conducted with population-based biobank data remain urgently needed, and follow-up RbG studies, which add substance to this research approach, remain solitary. In such studies, potentially disease-related genotypes are identified and individuals with those genotypes are recalled for consultation to gather more detailed clinical phenotypic information and explain to them the meaning of their genetic findings. Familial hypercholesterolemia (FH) is among the most common autosomal-dominant single-gene disorders, with a global prevalence of 1 in 500 (Nordestgaard et al., Eur. Heart J., 2013, 34 (45), 3478-3490). Untreated FH leads to lifelong elevated LDL cholesterol levels, which can cause ischemic heart disease, with potentially fatal consequences at a relatively early age. In most cases, the pathogenesis of FH is based on a defect in one of three LDL receptor-related genes-APOB, LDLR, and PCSK9. We present our first long-term follow-up RbG study of FH, conducted within the Estonian Biobank (34 recalled participants from a pilot RbG study and 291 controls harboring the same APOB, LDLR, and PCSK9 variants that were included in the pilot study). The participants' electronic health record data (FH-related diagnoses, lipid-lowering treatment prescriptions) and pharmacogenomic risk of developing statin-induced myopathy were assessed. A survey was administered to recalled participants to discern the impact of the knowledge of their genetic findings on their lives 4-6 years later. Significant differences in FH diagnoses and lipid-lowering treatment prescriptions were found between the recalled participants and controls (34 and 291 participants respectively). Our study highlights the need for more consistent lipid-lowering treatment adherence checkups and encourage more follow-up RbG studies to be performed.

Omics-informed CNV calls reduce false-positive rates and improve power for CNV-trait associations.

Copy-number variations (CNV) are believed to play an important role in a wide range of complex traits, but discovering such associations remains challenging. While whole-genome sequencing (WGS) is the gold-standard approach for CNV detection, there are several orders of magnitude more samples with available genotyping microarray data. Such array data can be exploited for CNV detection using dedicated software (e.g., PennCNV); however, these calls suffer from elevated false-positive and -negative rates. In this study, we developed a CNV quality score that weights PennCNV calls (pCNVs) based on their likelihood of being true positive. First, we established a measure of pCNV reliability by leveraging evidence from multiple omics data (WGS, transcriptomics, and methylomics) obtained from the same samples. Next, we built a predictor of omics-confirmed pCNVs, termed omics-informed quality score (OQS), using only PennCNV software output parameters. Promisingly, OQS assigned to pCNVs detected in close family members was up to 35% higher than the OQS of pCNVs not carried by other relatives (p < 3.0 × 10-90), outperforming other scores. Finally, in an association study of four anthropometric traits in 89,516 Estonian Biobank samples, the use of OQS led to a relative increase in the trait variance explained by CNVs of up to 56% compared with published quality filtering methods or scores. Overall, we put forward a flexible framework to improve any CNV detection method leveraging multi-omics evidence, applied it to improve PennCNV calls, and demonstrated its utility by improving the statistical power for downstream association analyses.

Spectrum and frequency of CHEK2 variants in breast cancer affected and general population in the Baltic states region, initial results and literature review.

BACKGROUND: While BRCA1/2 gene mutational spectrum and clinical features are widely studied, there is limited data on breast cancer-predisposing non-BRCA pathogenic/likely pathogenic variants (PV/LPVs) in the Baltic states region. According to previous studies, CHEK2 is the most frequent moderate-risk breast cancer predisposition gene. The study aimed to analyse the frequency and mutational spectrum of CHEK2 PV/LPVs in the Baltic states region and perform a literature review on the subject. METHODS: The study includes two cohorts - population-based Estonian biobank (EstBB) (N-152 349) and breast cancer affected cases from Latvia (N-105). In the cohort from Latvia, CHEK2, BRCA1, BRCA2, PALB2 testing with next-generation sequencing (NGS) was carried out in selected breast cancer cases. In the EstBB, the full SNP genotyped dataset Global Screening Array (GSA) (N-152 349) was used to screen CHEK2 PV/LPVs and variants c.319+2T > A (p.(?)), c.444+1G>A (p.(?)), c.433C > T (p.Arg145Trp), c.283C > T (p.Arg95*) in CHEK2 are reported from this dataset. In addition, a subset of the EstBB (N-4776) underwent whole-genome sequencing (WGS, N-2420) and whole-exome sequencing (WES, N-2356) and founder variants c.470T > C (p.Ile157Thr), c.444+1G>A (p.(?)), c.1100delC (p.Thr367Metfs*15) in CHEK2 were reported from this dataset. Moreover, a literature overview was performed on April 1, 2021, using the PubMed search of keywords 'CHEK2', 'breast cancer', 'Estonia', 'Lithuania', 'Latvia', 'Poland', 'Belarus' and 'Russia'. RESULTS: In the breast cancer affected cohort from Latvia 6 CHEK2 variants, classified as PV/LPVs, were observed (6/105; 5.7%), including recurrent ones c.470T > C (p.Ile157Thr) (1.9%) and del5395(ex9-10del; (p.Met304Leufs*16)) (1.9%), as well as single ones - c.1100delC (p.Thr367Metfs*15) (1%) and c.444+1G>A (p.(?)) (1%). From EstBB NGS data (N-4776) CHEK2 variant c.470T > C (p.Ile157Thr) was detected in 8.6% of cases, c.1100delC (p.Thr367Metfs*15) in 0.6% and c.444+1G>A (p.(?)) in 0.2% of cases. In the EstBB full cohort of SNP array data (N-152 349) CHEK2 variant c.444+1G>A (p.(?)) was detected in 0.02% of cases, c.319+2T > A (p.(?)) in 0.09% of cases, c.433C > T (p.Arg145Trp) in 0.02% of cases and c.283C > T (p.Arg95*) in <0.001% of cases. For the literature review altogether, 49 PubMed articles were found, 23 of which were relevant, representing CHEK2 PV/LPVs in the population of interest. Ten publications are from Poland, eight from Russia, three from Latvia and two from Belarus. CONCLUSIONS: This study is the first combined report on complete CHEK2 PV/LPVs screening in selected breast cancer affected cases in Latvia and large-scale population screening in Estonia, providing insight into the CHEK2 mutational spectrum in the Baltic states region. The initial results are in line with other studies that CHEK2 PV/LPVs frequency is around 5-6% of selected breast cancer cases. Here we report three CHEK2 PV/LPV - c.319+2T > A (p.(?)), c.433C > T (p.Arg145Trp), c.283C > T (p.Arg95*), that are novel for the Baltic states region. This is also the first report on c.1100delC (p.Thr367Metfs*15) and c.444+1G>A (p.(?)) from the Baltic states. High population frequency of c.470T > C (p. Ile157Thr) (8.6%) continues to question the variant's pathogenicity in particular populations. Other findings are concordant with previous reports from Latvia and neighbouring populations.

Identification of ALK in Thinness.

There is considerable inter-individual variability in susceptibility to weight gain despite an equally obesogenic environment in large parts of the world. Whereas many studies have focused on identifying the genetic susceptibility to obesity, we performed a GWAS on metabolically healthy thin individuals (lowest 6th percentile of the population-wide BMI spectrum) in a uniquely phenotyped Estonian cohort. We discovered anaplastic lymphoma kinase (ALK) as a candidate thinness gene. In Drosophila, RNAi mediated knockdown of Alk led to decreased triglyceride levels. In mice, genetic deletion of Alk resulted in thin animals with marked resistance to diet- and leptin-mutation-induced obesity. Mechanistically, we found that ALK expression in hypothalamic neurons controls energy expenditure via sympathetic control of adipose tissue lipolysis. Our genetic and mechanistic experiments identify ALK as a thinness gene, which is involved in the resistance to weight gain.

In vitro fertilization does not increase the incidence of de novo copy number alterations in fetal and placental lineages.

Although chromosomal instability (CIN) is a common phenomenon in cleavage-stage embryogenesis following in vitro fertilization (IVF)1-3, its rate in naturally conceived human embryos is unknown. CIN leads to mosaic embryos that contain a combination of genetically normal and abnormal cells, and is significantly higher in in vitro-produced preimplantation embryos as compared to in vivo-conceived preimplantation embryos4. Even though embryos with CIN-derived complex aneuploidies may arrest between the cleavage and blastocyst stages of embryogenesis5,6, a high number of embryos containing abnormal cells can pass this strong selection barrier7,8. However, neither the prevalence nor extent of CIN during prenatal development and at birth, following IVF treatment, is well understood. Here we profiled the genomic landscape of fetal and placental tissues postpartum from both IVF and naturally conceived children, to investigate the prevalence and persistence of large genetic aberrations that probably arose from IVF-related CIN. We demonstrate that CIN is not preserved at later stages of prenatal development, and that de novo numerical aberrations or large structural DNA imbalances occur at similar rates in IVF and naturally conceived live-born neonates. Our findings affirm that human IVF treatment has no detrimental effect on the chromosomal constitution of fetal and placental lineages.

Diverse phenotype in patients with complex I deficiency due to mutations in NDUFB11.

Mitochondrial complex I deficiency is the most frequent mitochondrial disorder presenting in childhood and the mutational spectrum is highly heterogeneous. The NDUFB11 gene is one of the recently identified genes, which is located in the short arm of the X-chromosome. Here we report clinical, biochemical, functional and genetic findings of two male patients with lactic acidosis, hypertrophic cardiomyopathy and isolated complex I deficiency due to de novo hemizygous mutations (c.286C > T and c.328C > T) in the NDUFB11 gene. Neither of them had any skin manifestations. The NDUFB11 gene encodes a relatively small integral membrane protein NDUFB11, which is essential for the assembly of an active complex I. The expression levels of this protein was decreased in both patient cells and a lentiviral complementation experiment also supported the notion that the complex I deficiency in those two patients is caused by NDUFB11 genetic defects. Our findings together with a review of the thirteen previously described patients demonstrate a wide spectrum of clinical features associated with NDUFB11-related complex I deficiency. However, histiocytoid cardiomyopathy and/or congenital sideroblastic anemia could be indicative for mutation in the NDUFB11 gene, while the clinical manifestation of the same mutation can be highly variable.

CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits.

There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01-0.2%), with large effects on height (>2.4 cm), weight (>5 kg), and body mass index (BMI) (>3.5 kg/m2). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m2 for each Mb of total deletion burden (P = 2.5 × 10-10, 6.0 × 10-5, and 2.9 × 10-3). Our study provides evidence that the same genes (e.g., MC4R, FIBIN, and FMO5) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders.Individual SNPs have small effects on anthropometric traits, yet the impact of CNVs has remained largely unknown. Here, Kutalik and co-workers perform a large-scale genome-wide meta-analysis of structural variation and find rare CNVs associated with height, weight and BMI with large effect sizes.

C14orf132 gene is possibly related to extremely low birth weight.

BACKGROUND: Despite extensive research the genetic component of extremely low birth weight (ELBW) in newborns has remained obscure. RESULTS: The aim of the case study was to identify candidate gene(s) causing ELBW in newborns and hypotrophy in infants. A family of four was studied: mother, father and two ELBW-phenotype children. Studies were made of the medical conditions of the second child at birth and post-partum - peculiar phenotype, micro-anomalies, recurrent infections, suspicion of autoimmune hepatitis, multifactorial encephalopathy and suspected metabolic and chromosomal abnormalities. Whole genome single nucleotide polymorphism (SNP) genotyping array was used to investigate the genomic rearrangements in both affected children using peripheral blood DNA samples. Whole blood transcriptome was assessed by using RNA sequencing (RNA-seq) in all four family members. RNA-seq identified a single gene - C14orf132 (chromosome 14 open reading frame 132) differentially expressed, with the level of the transcript significantly lower in the blood samples of the children. Copy number variant (CNV) analysis did not reveal any pathogenic CNVs in the region of C14orf132 gene of both affected children. CONCLUSION: We demonstrated the importance of combining whole genome CNV and transcriptome analysis in identification of the candidate gene(s) in case studies. We propose the C14orf132 gene expression to be associated with the ELBW-phenotype. C14orf132 gene is a novel long non-coding RNA (lincRNA) with unknown function, which might be associated with the pre- and early postnatal developmental delay through the altered gene expression.

De novo exonic mutation in MYH7 gene leading to exon skipping in a patient with early onset muscular weakness and fiber-type disproportion.

Here we report on a case of MYH7-related myopathy in a boy with early onset of muscular weakness and delayed motor development in infancy. His most affected muscles were neck extensors showing a dropped head sign, proximal muscles of lower limbs with positive Gower's sign, and trunk muscles. Brain and spinal cord MRI scans, echocardiography, and laboratory analyses including creatine kinase and lactate did not reveal any abnormalities. Muscle histopathology showed fiber-type disproportion. Whole exome sequencing of the parents-offspring trio revealed a novel de novo c.5655G>A p.(Ala1885=) synonymous substitution of the last nucleotide in exon 38 of the MYH7 gene. Further RNA investigations proved the skipping of exon 38 (p.1854_1885del). This is a first report of an exon-skipping mutation in the MYH7 gene causing myopathy. This report broadens both the phenotypic and genotypic spectra of MYH7-related myopathies.

Reporting incidental findings of genomic disorder-associated copy number variants to unselected biobank participants.

BACKGROUND: Procedural guidelines for disclosure of incidental genomic information are lacking. METHODS: We introduce a method and evaluated the impact of returning results to population biobank participants with 16p11.2 copy number variants, which are commonly associated with neurodevelopmental disorders and BMI imbalance. Of the 7877 participants, 11 carriers were detected. Eight participants were informed of their carrier status and surveyed 11-17 months later. RESULTS: All participants demonstrated preference for disclosure. Although two participants experienced worry, all five survey respondents rated receiving this information favorably. One participant reported modifications in treatment and three felt that their treatment/condition had since improved. CONCLUSION: This approach can be adapted and applied for the return of incidental findings to biobank participants.

Copy number variations and cognitive phenotypes in unselected populations.

IMPORTANCE: The association of copy number variations (CNVs), differing numbers of copies of genetic sequence at locations in the genome, with phenotypes such as intellectual disability has been almost exclusively evaluated using clinically ascertained cohorts. The contribution of these genetic variants to cognitive phenotypes in the general population remains unclear. OBJECTIVE: To investigate the clinical features conferred by CNVs associated with known syndromes in adult carriers without clinical preselection and to assess the genome-wide consequences of rare CNVs (frequency ≤0.05%; size ≥250 kilobase pairs [kb]) on carriers' educational attainment and intellectual disability prevalence in the general population. DESIGN, SETTING, AND PARTICIPANTS: The population biobank of Estonia contains 52,000 participants enrolled from 2002 through 2010. General practitioners examined participants and filled out a questionnaire of health- and lifestyle-related questions, as well as reported diagnoses. Copy number variant analysis was conducted on a random sample of 7877 individuals and genotype-phenotype associations with education and disease traits were evaluated. Our results were replicated on a high-functioning group of 993 Estonians and 3 geographically distinct populations in the United Kingdom, the United States, and Italy. MAIN OUTCOMES AND MEASURES: Phenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of these variants with educational attainment (from less than primary school through scientific degree) and prevalence of intellectual disability. RESULTS: Of the 7877 in the Estonian cohort, we identified 56 carriers of CNVs associated with known syndromes. Their phenotypes, including cognitive and psychiatric problems, epilepsy, neuropathies, obesity, and congenital malformations are similar to those described for carriers of identical rearrangements ascertained in clinical cohorts. A genome-wide evaluation of rare autosomal CNVs (frequency, ≤0.05%; ≥250 kb) identified 831 carriers (10.5%) of the screened general population. Eleven of 216 (5.1%) carriers of a deletion of at least 250 kb (odds ratio [OR], 3.16; 95% CI, 1.51-5.98; P = 1.5e-03) and 6 of 102 (5.9%) carriers of a duplication of at least 1 Mb (OR, 3.67; 95% CI, 1.29-8.54; P = .008) had an intellectual disability compared with 114 of 6819 (1.7%) in the Estonian cohort. The mean education attainment was 3.81 (P = 1.06e-04) among 248 (≥250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers (≥1 Mb). Of the deletion carriers, 33.5% did not graduate from high school (OR, 1.48; 95% CI, 1.12-1.95; P = .005) and 39.1% of duplication carriers did not graduate high school (OR, 1.89; 95% CI, 1.27-2.8; P = 1.6e-03). Evidence for an association between rare CNVs and lower educational attainment was supported by analyses of cohorts of adults from Italy and the United States and adolescents from the United Kingdom. CONCLUSIONS AND RELEVANCE: Known pathogenic CNVs in unselected, but assumed to be healthy, adult populations may be associated with unrecognized clinical sequelae. Additionally, individually rare but collectively common intermediate-size CNVs may be negatively associated with educational attainment. Replication of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health.

Whole-exome sequencing identifies de novo mutation in the COL1A1 gene to underlie the severe osteogenesis imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) comprises a clinically and genetically heterogeneous group of connective tissue disorders, characterized by low bone mass, increased bone fragility, and blue-gray eye sclera. OI often results from missense mutations in one of the conserved glycine residues present in the Gly-X-Y sequence repeats of the triple helical region of the collagen type I α chain, which is encoded by the COL1A1 gene. The aim of the present study is to describe the phenotype of OI II patient and a novel mutation, causing current phenotype. RESULTS: We report an undescribed de novo COL1A1 mutation in a patient affected by severe OI. After performing the whole-exome sequencing in a case parent-child trio, we identified a novel heterozygous c.2317G > T missense mutation in the COL1A1 gene, which leads to p.Gly773Cys transversion in the triple helical domain of the collagen type I α chain. The presence of the missense mutation was confirmed with the Sanger sequencing. CONCLUSIONS: Hereby, we report a novel mutation in the COL1A1 gene causing severe, life threatening OI and indicate the role of de novo mutation in the pathogenesis of rare familial diseases. Our study underlines the importance of exome sequencing in disease gene discovery for families where conventional genetic testing does not give conclusive evidence.

Syndromic intellectual disability: a new phenotype caused by an aromatic amino acid decarboxylase gene (DDC) variant.

The causative variant in a consanguineous family in which the three patients (two siblings and a cousin) presented with intellectual disability, Marfanoid habitus, craniofacial dysmorphisms, chronic diarrhea and progressive kyphoscoliosis, has been identified through whole exome sequencing (WES) analysis. WES study identified a homozygous DDC variant in the patients, c.1123C>T, resulting in p.Arg375Cys missense substitution. Mutations in DDC cause a recessive metabolic disorder (aromatic amino acid decarboxylase, AADC, deficiency, OMIM #608643) characterized by hypotonia, oculogyric crises, excessive sweating, temperature instability, dystonia, severe neurologic dysfunction in infancy, and specific abnormalities of neurotransmitters and their metabolites in the cerebrospinal fluid (CSF). In our family, analysis of neurotransmitters and their metabolites in patient's CSF shows a pattern compatible with AADC deficiency, although the clinical signs are different from the classic form. Our work expands the phenotypic spectrum associated with DDC variants, which therefore can cause an additional novel syndrome without typical movement abnormalities.

The Diagnostic Utility of Single Long Contiguous Stretches of Homozygosity in Patients without Parental Consanguinity.

We present data from our clinical department's experience with chromosomal microarray analysis (CMA) regarding the diagnostic utility of 1 or 2 long contiguous stretches of homozygosity (LCSHs) in an outbred population. The study group consisted of 2,110 consecutive patients from 2011 to 2014 for whom CMA was performed. The minimum cut-off size for defining a homozygous stretch was 5 Mb. To focus on cases with no parental consanguinity, we further studied only patients in whom the total length of homozygous stretches did not exceed 28 Mb or 1% of the autosomal genome length. We identified 6 chromosomal regions where homozygous stretches appeared in at least 3 patients and excluded these from further analysis. In 2 out of 120 patients with an isolated finding of 1 or 2 non-recurrent LCSHs, a plausible candidate gene associated with their phenotype was identified within the homozygous stretch. In both of these cases, a pathogenic mutation was detected, leading to diagnoses of pyruvate kinase deficiency and Marinesco-Sjögren syndrome. To clarify whether previously found homozygous stretches could be important for the interpretation of genome-wide sequencing data, we report 7 cases in which homozygous stretches not encompassing a clinically associated gene were first found on CMA, followed by the diagnostic whole-exome sequencing. The diagnostic utility of single LCSHs, unlikely to be caused by uniparental disomy, is discussed in detail.