Publications by authors named "Francesca Forzano"

58 Publications

Editorial: Overlapping Phenotypes and Genetic Heterogeneity of Rare Neurodevelopmental Disorders.

Front Neurol 2021 22;12:711288. Epub 2021 Jul 22.

Research Laboratory of Medical Cytogenetics and Molecular Genetics, Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.

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http://dx.doi.org/10.3389/fneur.2021.711288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341807PMC
July 2021

Copy number variation analysis implicates novel pathways in patients with oculo-auriculo-vertebral-spectrum and congenital heart defects.

Clin Genet 2021 09 24;100(3):268-279. Epub 2021 May 24.

Department of Pediatrics, Obstetrics and Gynecology, "Sapienza" University of Rome, Rome, Italy.

Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder of craniofacial morphogenesis. Its etiology is unclear, but assumed to be complex and heterogeneous, with contribution of both genetic and environmental factors. We assessed the occurrence of copy number variants (CNVs) in a cohort of 19 unrelated OAVS individuals with congenital heart defect. Chromosomal microarray analysis identified pathogenic CNVs in 2/19 (10.5%) individuals, and CNVs classified as variants of uncertain significance in 7/19 (36.9%) individuals. Remarkably, two subjects had small intragenic CNVs involving DACH1 and DACH2, two paralogs coding for key components of the PAX-SIX-EYA-DACH network, a transcriptional regulatory pathway controlling developmental processes relevant to OAVS and causally associated with syndromes characterized by craniofacial involvement. Moreover, a third patient showed a large duplication encompassing DMBX1/OTX3, encoding a transcriptional repressor of OTX2, another transcription factor functionally connected to the DACH-EYA-PAX network. Among the other relevant CNVs, a deletion encompassing HSD17B6, a gene connected with the retinoic acid signaling pathway, whose dysregulation has been implicated in craniofacial malformations, was also identified. Our findings suggest that CNVs affecting gene dosage likely contribute to the genetic heterogeneity of OAVS, and implicate the PAX-SIX-EYA-DACH network as novel pathway involved in the etiology of this developmental trait.
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http://dx.doi.org/10.1111/cge.13994DOI Listing
September 2021

8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature.

Genes (Basel) 2021 04 27;12(5). Epub 2021 Apr 27.

Istituto Auxologico Italiano, IRCCS, Laboratory of Medical Cytogenetics and Molecular Genetics, 20145 Milan, Italy.

To date only five patients with 8p23.2-pter microdeletions manifesting a mild-to-moderate cognitive impairment and/or developmental delay, dysmorphisms and neurobehavioral issues were reported. The smallest microdeletion described by Wu in 2010 suggested a critical region (CR) of 2.1 Mb including several genes, out of which , , , and are the main candidates. Here we present seven additional patients with 8p23.2-pter microdeletions, ranging from 71.79 kb to 4.55 Mb. The review of five previously reported and nine Decipher patients confirmed the association of the CR with a variable clinical phenotype characterized by intellectual disability/developmental delay, including language and speech delay and/or motor impairment, behavioral anomalies, autism spectrum disorder, dysmorphisms, microcephaly, fingers/toes anomalies and epilepsy. Genotype analysis allowed to narrow down the 8p23.3 candidate region which includes only , and genes, accounting for the main signs of the broad clinical phenotype associated to 8p23.2-pter microdeletions. This region is more restricted compared to the previously proposed CR. Overall, our data favor the hypothesis that is the actual strongest candidate for neurodevelopmental/behavioral phenotypes. Additional patients will be necessary to validate the pathogenic role of and better define how the two contiguous genes, and , might contribute to the clinical phenotype.
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http://dx.doi.org/10.3390/genes12050652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146486PMC
April 2021

Genome-Wide DNA Methylation Analysis of a Cohort of 41 Patients Affected by Oculo-Auriculo-Vertebral Spectrum (OAVS).

Int J Mol Sci 2021 Jan 26;22(3). Epub 2021 Jan 26.

Istituto Auxologico Italiano IRCCS, Bioinformatics and Statistical Genomics Unit, Cusano Milanino, 20095 Milano, Italy.

Oculo-auriculo-vertebral-spectrum (OAVS; OMIM 164210) is a rare disorder originating from abnormal development of the first and second branchial arch. The clinical phenotype is extremely heterogeneous with ear anomalies, hemifacial microsomia, ocular defects, and vertebral malformations being the main features. , , and gene variants were reported in a few OAVS patients, but the etiology remains largely unknown. A multifactorial origin has been proposed, including the involvement of environmental and epigenetic mechanisms. To identify the epigenetic mechanisms contributing to OAVS, we evaluated the DNA-methylation profiles of 41 OAVS unrelated affected individuals by using a genome-wide microarray-based methylation approach. The analysis was first carried out comparing OAVS patients with controls at the group level. It revealed a moderate epigenetic variation in a large number of genes implicated in basic chromatin dynamics such as DNA packaging and protein-DNA organization. The alternative analysis in individual profiles based on the searching for Stochastic Epigenetic Variants (SEV) identified an increased number of SEVs in OAVS patients compared to controls. Although no recurrent deregulated enriched regions were found, isolated patients harboring suggestive epigenetic deregulations were identified. The recognition of a different DNA methylation pattern in the OAVS cohort and the identification of isolated patients with suggestive epigenetic variations provide consistent evidence for the contribution of epigenetic mechanisms to the etiology of this complex and heterogeneous disorder.
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http://dx.doi.org/10.3390/ijms22031190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866060PMC
January 2021

ESHG warns against misuses of genetic tests and biobanks for discrimination purposes.

Eur J Hum Genet 2021 Jun 18;29(6):894-896. Epub 2021 Jan 18.

ESAT-STADIUS, KU Leuven - University of Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1038/s41431-020-00786-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187659PMC
June 2021

Opportunistic genomic screening. Recommendations of the European Society of Human Genetics.

Eur J Hum Genet 2021 03 22;29(3):365-377. Epub 2020 Nov 22.

Clinical Genetics Department, Guy's & St Thomas' NHS Foundation Trust, London, UK.

If genome sequencing is performed in health care, in theory the opportunity arises to take a further look at the data: opportunistic genomic screening (OGS). The European Society of Human Genetics (ESHG) in 2013 recommended that genome analysis should be restricted to the original health problem at least for the time being. Other organizations have argued that 'actionable' genetic variants should or could be reported (including American College of Medical Genetics and Genomics, French Society of Predictive and Personalized Medicine, Genomics England). They argue that the opportunity should be used to routinely and systematically look for secondary findings-so-called opportunistic screening. From a normative perspective, the distinguishing characteristic of screening is not so much its context (whether public health or health care), but the lack of an indication for having this specific test or investigation in those to whom screening is offered. Screening entails a more precarious benefits-to-risks balance. The ESHG continues to recommend a cautious approach to opportunistic screening. Proportionality and autonomy must be guaranteed, and in collectively funded health-care systems the potential benefits must be balanced against health care expenditures. With regard to genome sequencing in pediatrics, ESHG argues that it is premature to look for later-onset conditions in children. Counseling should be offered and informed consent is and should be a central ethical norm. Depending on developing evidence on penetrance, actionability, and available resources, OGS pilots may be justified to generate data for a future, informed, comparative analysis of OGS and its main alternatives, such as cascade testing.
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http://dx.doi.org/10.1038/s41431-020-00758-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940405PMC
March 2021

P5CS expression study in a new family with ALDH18A1-associated hereditary spastic paraplegia SPG9.

Ann Clin Transl Neurol 2019 08 19;6(8):1533-1540. Epub 2019 Jul 19.

Medical Genetics Unit, S. Orsola-Malpighi Hospital, Bologna, Italy.

In 2015-2016, we and others reported ALDH18A1 mutations causing dominant (SPG9A) or recessive (SPG9B) spastic paraplegia. In vitro production of the ALDH18A1 product, Δ -pyrroline-5-carboxylate synthetase (P5CS), appeared necessary for cracking SPG9 disease-causing mechanisms. We now describe a baculovirus-insect cell system that yields mgs of pure human P5CS and that has proven highly valuable with two novel P5CS mutations reported here in new SPG9B patients. We conclude that both mutations are disease-causing, that SPG9B associates with partial P5CS deficiency and that it is clinically more severe than SPG9A, as reflected in onset age, disability, cognitive status, growth, and dysmorphic traits.
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http://dx.doi.org/10.1002/acn3.50821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689680PMC
August 2019

European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death.

Eur J Hum Genet 2019 12 24;27(12):1763-1773. Epub 2019 Jun 24.

Section Community Genetics, Department of Clinical Genetics and Amsterdam Public Health research institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Sudden cardiac death (SCD) accounts for 10-20% of total mortality, i.e., one in five individuals will eventually die suddenly. Given the substantial genetic component of SCD in younger cases, postmortem genetic testing may be particularly useful in elucidating etiological factors in the cause of death in this subset. The identification of genes responsible for inherited cardiac diseases have led to the organization of cardiogenetic consultations in many countries worldwide. Expert recommendations are available, emphasizing the importance of genetic testing and appropriate information provision of affected individuals, as well as their relatives. However, the context of postmortem genetic testing raises some particular ethical, legal, and practical (including economic or financial) challenges. The Public and Professional Policy Committee of the European Society of Human Genetics (ESHG), together with international experts, developed recommendations on management of SCD after a workshop sponsored by the Brocher Foundation and ESHG in November 2016. These recommendations have been endorsed by the ESHG Board, the European Council of Legal Medicine, the European Society of Cardiology working group on myocardial and pericardial diseases, the ERN GUARD-HEART, and the Association for European Cardiovascular Pathology. They emphasize the importance of increasing the proportion of both medical and medicolegal autopsies and educating the professionals. Multidisciplinary collaboration is of utmost importance. Public funding should be allocated to reach these goals and allow public health evaluation.
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http://dx.doi.org/10.1038/s41431-019-0445-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6870982PMC
December 2019

Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome.

Clin Genet 2019 06 3;95(6):693-703. Epub 2019 Apr 3.

Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1-associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly-acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound-heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss-of-function mutations in NEB, consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities (P = 0.0005), supporting a causal role for LZTR1. Second, targeted sequencing of eight unsolved NS-like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.-38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1-4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected.
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http://dx.doi.org/10.1111/cge.13533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563422PMC
June 2019

Reply to Bombard and Mighton.

Eur J Hum Genet 2019 04 18;27(4):507-508. Epub 2019 Jan 18.

Clinical Genetics Department, Guy's & St Thomas' NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1038/s41431-018-0315-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460587PMC
April 2019

Nablus syndrome: Easy to diagnose yet difficult to solve.

Am J Med Genet C Semin Med Genet 2018 12;178(4):447-457

Department of Genetics, CHEO, Ottawa, Ontario, Canada.

Nablus syndrome was first described by the late Ahmad Teebi in 2000, and 13 individuals have been reported to date. Nablus syndrome can be clinically diagnosed based on striking facial features, including tight glistening skin with reduced facial expression, blepharophimosis, telecanthus, bulky nasal tip, abnormal external ear architecture, upswept frontal hairline, and sparse eyebrows. However, the precise genetic etiology for this rare condition remains elusive. Comparative microarray analyses of individuals with Nablus syndrome (including two mother-son pairs) reveal an overlapping 8q22.1 microdeletion, with a minimal critical region of 1.84 Mb (94.43-96.27 Mb). Whereas this deletion is present in all affected individuals, 13 individuals without Nablus syndrome (including two mother-child pairs) also have the 8q22.1 microdeletion that partially or fully overlaps the minimal critical region. Thus, the 8q22.1 microdeletion is necessary but not sufficient to cause the clinical features characteristic of Nablus syndrome. We discuss possible explanations for Nablus syndrome, including one-locus, two-locus, epigenetic, and environmental mechanisms. We performed exome sequencing for five individuals with Nablus syndrome. Although we failed to identify any deleterious rare coding variants in the critical region that were shared between individuals, we did identify one common SNP in an intronic region that was shared. Clearly, unraveling the genetic mechanism(s) of Nablus syndrome will require additional investigation, including genomic and RNA sequencing of a larger cohort of affected individuals. If successful, it will provide important insights into fundamental concepts such as variable expressivity, incomplete penetrance, and complex disease relevant to both Mendelian and non-Mendelian disorders.
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http://dx.doi.org/10.1002/ajmg.c.31660DOI Listing
December 2018

FXS-Like Phenotype in Two Unrelated Patients Carrying a Methylated Premutation of the Gene.

Front Genet 2018 2;9:442. Epub 2018 Nov 2.

Center for Human Genetics, KU Leuven, Leuven, Belgium.

Fragile X syndrome (FXS) is mostly caused by two distinct events that occur in the gene (Xq27.3): an expansion above 200 repeats of a CGG triplet located in the 5'UTR of the gene, and methylation of the cytosines located in the CpG islands upstream of the CGG repeats. Here, we describe two unrelated families with one FXS child and another sibling presenting mild intellectual disability and behavioral features evocative of FXS. Genetic characterization of the undiagnosed sibling revealed mosaicism in both the CGG expansion size and the methylation levels in the different tissues analyzed. This report shows that in the same family, two siblings carrying different CGG repeats, one in the full-mutation range and the other in the premutation range, present methylation mosaicism and consequent decreased FMRP production leading to FXS and FXS-like features, respectively. Decreased FMRP levels, more than the number of repeats seem to correlate with the severity of FXS clinical phenotypes.
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http://dx.doi.org/10.3389/fgene.2018.00442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224343PMC
November 2018

Lowry-Wood syndrome: further evidence of association with RNU4ATAC, and correlation between genotype and phenotype.

Hum Genet 2018 Dec 27;137(11-12):905-909. Epub 2018 Oct 27.

Divisions of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada.

Lowry-Wood syndrome (LWS) is a skeletal dysplasia characterized by multiple epiphyseal dysplasia associated with microcephaly, developmental delay and intellectual disability, and eye involvement. Pathogenic variants in RNU4ATAC, an RNA of the minor spliceosome important for the excision of U12-dependent introns, have been recently associated with LWS. This gene had previously also been associated with microcephalic osteodysplastic primordial dwarfism (MOPD) and Roifman syndrome (RS), two distinct conditions which share with LWS some skeletal and neurological anomalies. We performed exome sequencing in two individuals with Lowry-Wood syndrome. We report RNU4ATAC pathogenic variants in two further patients. Moreover, an analysis of all RNU4ATAC variants reported so far showed that FitCons scores for nucleotides mutated in the more severe MOPD are higher than RS or LWS and that they were more frequently located in the 5' Stem-Loop of the RNA critical for the formation of the U4/U6.U5 tri-snRNP complex, whereas the variants are more dispersed in the other conditions. We are thus confirming that RNU4ATAC is the gene responsible for LWS and provide a genotype-phenotype correlation analysis.
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http://dx.doi.org/10.1007/s00439-018-1950-8DOI Listing
December 2018

Recontacting patients in clinical genetics services: recommendations of the European Society of Human Genetics.

Eur J Hum Genet 2019 02 11;27(2):169-182. Epub 2018 Oct 11.

Clinical Genetics Department, Guy's & St. Thomas' NHS Foundation Trust, London, UK.

Technological advances have increased the availability of genomic data in research and the clinic. If, over time, interpretation of the significance of the data changes, or new information becomes available, the question arises as to whether recontacting the patient and/or family is indicated. The Public and Professional Policy Committee of the European Society of Human Genetics (ESHG), together with research groups from the UK and the Netherlands, developed recommendations on recontacting which, after public consultation, have been endorsed by ESHG Board. In clinical genetics, recontacting for updating patients with new, clinically significant information related to their diagnosis or previous genetic testing may be justifiable and, where possible, desirable. Consensus about the type of information that should trigger recontacting converges around its clinical and personal utility. The organization of recontacting procedures and policies in current health care systems is challenging. It should be sustainable, commensurate with previously obtained consent, and a shared responsibility between healthcare providers, laboratories, patients, and other stakeholders. Optimal use of the limited clinical resources currently available is needed. Allocation of dedicated resources for recontacting should be considered. Finally, there is a need for more evidence, including economic and utility of information for people, to inform which strategies provide the most cost-effective use of healthcare resources for recontacting.
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http://dx.doi.org/10.1038/s41431-018-0285-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336881PMC
February 2019

A response to the forensic genetics policy initiative's report "Establishing Best Practice for Forensic DNA Databases".

Forensic Sci Int Genet 2018 09 5;36:e19-e21. Epub 2018 Jul 5.

Department of Political Science, University of Vienna, Austria; Department of Global Health & Social Medicine, King's College London, UK. Electronic address:

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http://dx.doi.org/10.1016/j.fsigen.2018.07.002DOI Listing
September 2018

Recontacting or not recontacting? A survey of current practices in clinical genetics centres in Europe.

Eur J Hum Genet 2018 07 23;26(7):946-954. Epub 2018 Apr 23.

Egenis, University of Exeter, Exeter, UK.

Advances in genomic medicine are improving diagnosis and treatment of some health conditions, and the question of whether former patients should be recontacted is therefore timely. The issue of recontacting is becoming more important with increased integration of genomics in 'mainstream' medicine. Empirical evidence is needed to advance the discussion over whether and how recontacting should be implemented. We administered a web-based survey to genetic services in European countries to collect information about existing infrastructures and practices relevant to recontacting patients. The majority of the centres stated they had recontacted patients to update them about new significant information; however, there were no standardised practices or systems in place. There was also a multiplicity of understandings of the term 'recontacting', which respondents conflated with routine follow-up programmes, or even with post-test counselling. Participants thought that recontacting systems should be implemented to provide the best service to the patients and families. Nevertheless, many barriers to implementation were mentioned. These included: lack of resources and infrastructure, concerns about potential negative psychological consequences of recontacting, unclear operational definitions of recontacting, policies that prevent healthcare professionals from recontacting, and difficulties in locating patients after their last contact. These barriers are also intensified by the highly variable development (and establishment) of the specialties of medical genetics and genetic counselling across different European countries. Future recommendations about recontacting need to consider these barriers. It is also important to reach an 'operational definition' that can be useful in different countries.
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http://dx.doi.org/10.1038/s41431-018-0131-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018700PMC
July 2018

Responsible innovation in human germline gene editing: Background document to the recommendations of ESHG and ESHRE.

Eur J Hum Genet 2018 04 12;26(4):450-470. Epub 2018 Jan 12.

Department of Clinical Genetics, Section Community Genetics and Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, The Netherlands.

Technological developments in gene editing raise high expectations for clinical applications, including editing of the germline. The European Society of Human Reproduction and Embryology (ESHRE) and the European Society of Human Genetics (ESHG) together developed a Background document and Recommendations to inform and stimulate ongoing societal debates. This document provides the background to the Recommendations. Germline gene editing is currently not allowed in many countries. This makes clinical applications in these countries impossible now, even if germline gene editing would become safe and effective. What were the arguments behind this legislation, and are they still convincing? If a technique could help to avoid serious genetic disorders, in a safe and effective way, would this be a reason to reconsider earlier standpoints? This Background document summarizes the scientific developments and expectations regarding germline gene editing, legal regulations at the European level, and ethics for three different settings (basic research, preclinical research and clinical applications). In ethical terms, we argue that the deontological objections (e.g., gene editing goes against nature) do not seem convincing while consequentialist objections (e.g., safety for the children thus conceived and following generations) require research, not all of which is allowed in the current legal situation in European countries. Development of this Background document and Recommendations reflects the responsibility to help society understand and debate the full range of possible implications of the new technologies, and to contribute to regulations that are adapted to the dynamics of the field while taking account of ethical considerations and societal concerns.
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http://dx.doi.org/10.1038/s41431-017-0077-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891502PMC
April 2018

Human germline gene editing: Recommendations of ESHG and ESHRE.

Eur J Hum Genet 2018 04 12;26(4):445-449. Epub 2018 Jan 12.

Department of Clinical Genetics, Section Community Genetics, and Amsterdam Public Health research institute, VU University Medical Center, Amsterdam, The Netherlands.

Technological developments in gene editing raise high expectations for clinical applications, first of all for somatic gene editing but in theory also for germline gene editing (GLGE). GLGE is currently not allowed in many countries. This makes clinical applications in these countries impossible now, even if GLGE would become safe and effective. What were the arguments behind this legislation, and are they still convincing? If a technique can help to avoid serious genetic disorders, in a safe and effective way, would this be a reason to reconsider earlier standpoints? The European Society of Human Reproduction and Embryology (ESHRE) and the European Society of Human Genetics (ESHG) together developed a Background document and Recommendations to inform and stimulate ongoing societal debates. After consulting its membership and experts, this final version of the Recommendations was endorsed by the Executive Committee and the Board of the respective Societies in May 2017. Taking account of ethical arguments, we argue that both basic and pre-clinical research regarding GLGE can be justified, with conditions. Furthermore, while clinical GLGE would be totally premature, it might become a responsible intervention in the future, but only after adequate pre-clinical research. Safety of the child and future generations is a major concern. Future discussions must also address priorities among reproductive and potential non-reproductive alternatives, such as PGD and somatic editing, if that would be safe and successful. The prohibition of human germline modification, however, needs renewed discussion among relevant stakeholders, including the general public and legislators.
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http://dx.doi.org/10.1038/s41431-017-0076-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891496PMC
April 2018

Human germline gene editing. Recommendations of ESHG and ESHRE.

Hum Reprod Open 2018 12;2018(1):hox025. Epub 2018 Jan 12.

Department of Clinical Genetics, Section Community Genetics, and Amsterdam Public Health Research Institute, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.

Technological developments in gene editing raise high expectations for clinical applications, first of all for somatic gene editing but in theory also for germline gene editing (GLGE). GLGE is currently not allowed in many countries. This makes clinical applications in these countries impossible now, even if GLGE would become safe and effective. What were the arguments behind this legislation, and are they still convincing? If a technique can help to avoid serious genetic disorders, in a safe and effective way, would this be a reason to reconsider earlier standpoints? The European Society of Human Reproduction and Embryology (ESHRE) and the European Society of Human Genetics (ESHG) together developed a Background document and Recommendations to inform and stimulate ongoing societal debates. After consulting its membership and experts, this final version of the Recommendations was endorsed by the Executive Committee and the Board of the respective Societies in May 2017. Taking account of ethical arguments, we argue that both basic and pre-clinical research regarding human GLGE can be justified, with conditions. Furthermore, while clinical GLGE would be totally premature, it might become a responsible intervention in the future, but only after adequate pre-clinical research. Safety of the child and future generations is a major concern. Future discussions must also address priorities among reproductive and potential non-reproductive alternatives, such as PGD and somatic editing, if that would be safe and successful. The prohibition of human germline modification, however, needs renewed discussion among relevant stakeholders, including the general public and legislators.
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http://dx.doi.org/10.1093/hropen/hox025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276661PMC
January 2018

Responsible innovation in human germline gene editing. Background document to the recommendations of ESHG and ESHRE.

Hum Reprod Open 2018 12;2018(1):hox024. Epub 2018 Jan 12.

Department of Clinical Genetics, Section Community Genetics, and Amsterdam Public Health Research Institute, VU University Medical Center, Van der Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands.

Technological developments in gene editing raise high expectations for clinical applications, including editing of the germline. The European Society of Human Reproduction and Embryology (ESHRE) and the European Society of Human Genetics (ESHG) together developed a Background document and Recommendations to inform and stimulate ongoing societal debates. This document provides the background to the Recommendations. Germline gene editing is currently not allowed in many countries. This makes clinical applications in these countries impossible now, even if germline gene editing would become safe and effective. What were the arguments behind this legislation, and are they still convincing? If a technique could help to avoid serious genetic disorders, in a safe and effective way, would this be a reason to reconsider earlier standpoints? This Background document summarizes the scientific developments and expectations regarding germline gene editing, legal regulations at the European level, and ethics for three different settings (basic research, pre-clinical research and clinical applications). In ethical terms, we argue that the deontological objections (e.g. gene editing goes against nature) do not seem convincing while consequentialist objections (e.g. safety for the children thus conceived and following generations) require research, not all of which is allowed in the current legal situation in European countries. Development of this Background document and Recommendations reflects the responsibility to help society understand and debate the full range of possible implications of the new technologies, and to contribute to regulations that are adapted to the dynamics of the field while taking account of ethical considerations and societal concerns.
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http://dx.doi.org/10.1093/hropen/hox024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276657PMC
January 2018

One small edit for humans, one giant edit for humankind? Points and questions to consider for a responsible way forward for gene editing in humans.

Eur J Hum Genet 2018 01 30;26(1):1-11. Epub 2017 Nov 30.

Department of Clinical Genetics, Section Community Genetics and EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands.

Gene editing, which allows for specific location(s) in the genome to be targeted and altered by deleting, adding or substituting nucleotides, is currently the subject of important academic and policy discussions. With the advent of efficient tools, such as CRISPR-Cas9, the plausibility of using gene editing safely in humans for either somatic or germ line gene editing is being considered seriously. Beyond safety issues, somatic gene editing in humans does raise ethical, legal and social issues (ELSI), however, it is suggested to be less challenging to existing ethical and legal frameworks; indeed somatic gene editing is already applied in (pre-) clinical trials. In contrast, the notion of altering the germ line or embryo such that alterations could be heritable in humans raises a large number of ELSI; it is currently debated whether it should even be allowed in the context of basic research. Even greater ELSI debates address the potential use of germ line or embryo gene editing for clinical purposes, which, at the moment is not being conducted and is prohibited in several jurisdictions. In the context of these ongoing debates surrounding gene editing, we present herein guidance to further discussion and investigation by highlighting three crucial areas that merit the most attention, time and resources at this stage in the responsible development and use of gene editing technologies: (1) conducting careful scientific research and disseminating results to build a solid evidence base; (2) conducting ethical, legal and social issues research; and (3) conducting meaningful stakeholder engagement, education and dialogue.
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http://dx.doi.org/10.1038/s41431-017-0024-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839051PMC
January 2018

BGN Mutations in X-Linked Spondyloepimetaphyseal Dysplasia.

Am J Hum Genet 2016 06 26;98(6):1243-1248. Epub 2016 May 26.

Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea. Electronic address:

Spondyloepimetaphyseal dysplasias (SEMDs) comprise a heterogeneous group of autosomal-dominant and autosomal-recessive disorders. An apparent X-linked recessive (XLR) form of SEMD in a single Italian family was previously reported. We have been able to restudy this family together with a second family from Korea by segregating a severe SEMD in an X-linked pattern. Exome sequencing showed missense mutations in BGN c.439A>G (p.Lys147Glu) in the Korean family and c.776G>T (p.Gly259Val) in the Italian family; the c.439A>G (p.Lys147Glu) mutation was also identified in a further simplex SEMD case from India. Biglycan is an extracellular matrix proteoglycan that can bind transforming growth factor beta (TGF-β) and thus regulate its free concentration. In 3-dimensional simulation, both altered residues localized to the concave arc of leucine-rich repeat domains of biglycan that interact with TGF-β. The observation of recurrent BGN mutations in XLR SEMD individuals from different ethnic backgrounds allows us to define "XLR SEMD, BGN type" as a nosologic entity.
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http://dx.doi.org/10.1016/j.ajhg.2016.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908150PMC
June 2016

Responsible implementation of expanded carrier screening.

Eur J Hum Genet 2016 06 16;24(6):e1-e12. Epub 2016 Mar 16.

Clinical Institute of Medical Genetics, Ljubljana University Medical Centre, Ljubljana, Slovenia.

This document of the European Society of Human Genetics contains recommendations regarding responsible implementation of expanded carrier screening. Carrier screening is defined here as the detection of carrier status of recessive diseases in couples or persons who do not have an a priori increased risk of being a carrier based on their or their partners' personal or family history. Expanded carrier screening offers carrier screening for multiple autosomal and X-linked recessive disorders, facilitated by new genetic testing technologies, and allows testing of individuals regardless of ancestry or geographic origin. Carrier screening aims to identify couples who have an increased risk of having an affected child in order to facilitate informed reproductive decision making. In previous decades, carrier screening was typically performed for one or few relatively common recessive disorders associated with significant morbidity, reduced life-expectancy and often because of a considerable higher carrier frequency in a specific population for certain diseases. New genetic testing technologies enable the expansion of screening to multiple conditions, genes or sequence variants. Expanded carrier screening panels that have been introduced to date have been advertised and offered to health care professionals and the public on a commercial basis. This document discusses the challenges that expanded carrier screening might pose in the context of the lessons learnt from decades of population-based carrier screening and in the context of existing screening criteria. It aims to contribute to the public and professional discussion and to arrive at better clinical and laboratory practice guidelines.
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http://dx.doi.org/10.1038/ejhg.2015.271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867464PMC
June 2016

A specific mutation in TBL1XR1 causes Pierpont syndrome.

J Med Genet 2016 05 14;53(5):330-7. Epub 2016 Jan 14.

Department of Paediatrics, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.

Background: The combination of developmental delay, facial characteristics, hearing loss and abnormal fat distribution in the distal limbs is known as Pierpont syndrome. The aim of the present study was to detect and study the cause of Pierpont syndrome.

Methods: We used whole-exome sequencing to analyse four unrelated individuals with Pierpont syndrome, and Sanger sequencing in two other unrelated affected individuals. Expression of mRNA of the wild-type candidate gene was analysed in human postmortem brain specimens, adipose tissue, muscle and liver. Expression of RNA in lymphocytes in patients and controls was additionally analysed. The variant protein was expressed in, and purified from, HEK293 cells to assess its effect on protein folding and function.

Results: We identified a single heterozygous missense variant, c.1337A>G (p.Tyr446Cys), in transducin β-like 1 X-linked receptor 1 (TBL1XR1) as disease-causing in all patients. TBL1XR1 mRNA expression was demonstrated in pituitary, hypothalamus, white and brown adipose tissue, muscle and liver. mRNA expression is lower in lymphocytes of two patients compared with the four controls. The mutant TBL1XR1 protein assembled correctly into the nuclear receptor corepressor (NCoR)/ silencing mediator for retinoid and thyroid receptors (SMRT) complex, suggesting a dominant-negative mechanism. This contrasts with loss-of-function germline TBL1XR1 deletions and other TBL1XR1 mutations that have been implicated in autism. However, autism is not present in individuals with Pierpont syndrome.

Conclusions: This study identifies a specific TBL1XR1 mutation as the cause of Pierpont syndrome. Deletions and other mutations in TBL1XR1 can cause autism. The marked differences between Pierpont patients with the p.Tyr446Cys mutation and individuals with other mutations and whole gene deletions indicate a specific, but as yet unknown, disease mechanism of the TBL1XR1 p.Tyr446Cys mutation.
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http://dx.doi.org/10.1136/jmedgenet-2015-103233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853543PMC
May 2016

Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities.

JAMA Psychiatry 2016 Jan;73(1):20-30

Service de Génétique Médicale, Faculté de Médecine, Centre Hospitalier Universitaire (CHU) Nantes, Institut National de la Santé et de la Recherche Medicale (INSERM) Unités Mixtes de Recherche 957, Nantes, France26Service de Génétique Médicale, CHU de Bor.

Importance: The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI).

Objectives: To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD.

Design, Setting, And Participants: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives.

Main Outcomes And Measures: Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data.

Results: Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies.

Conclusions And Relevance: The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.
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http://dx.doi.org/10.1001/jamapsychiatry.2015.2123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894477PMC
January 2016
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