Various haploinsufficiency mechanisms in Pitt-Hopkins syndrome.
Abstract Pitt-Hopkins syndrome is a rare neurodevelopment disorder caused by haploinsufficiency of the transcription factor 4 (TCF4). The main clinical symptoms of Pitt-Hopkins syndrome are severe development delay, intellectual disability, characteristic facial phenotype and breathing abnormalities, including episodic hyperventilation. Different pathogenic variants can lead to Pitt-Hopkins syndrome. The most common are large deletions at 18q21 encompassing the TCF4 gene and frameshifting/nonsense single nucleotide variants. However, variants in noncoding regions can also lead to Pitt-Hopkins syndrome by disruptin...
Source: European Journal of Medical Genetics - October 15, 2020 Category: Genetics & Stem Cells Authors: Sparber P, Filatova A, Anisimova I, Markova T, Voinova V, Chuhrova A, Tabakov V, Skoblov M Tags: Eur J Med Genet Source Type: research

The tip of the iceberg for diagnostic dilemmas: performance of current diagnostics and future complementary screening approaches.
Abstract Genetic testing is currently the leading edge of clinical care when it comes to diagnostics. However, many questions remain unanswered even when employing next-generation sequencing techniques due to our inability to decode genetic variations and our limited repertoire of available diagnoses. Accordingly, diagnostic yields for current genomic screenings are
Source: European Journal of Medical Genetics - October 15, 2020 Category: Genetics & Stem Cells Authors: Bastos PAD, Barbosa R Tags: Eur J Med Genet Source Type: research

MUTYH-associated polyposis: review and update of the French recommendations established in 2012 under the auspices of the National Cancer Institute (INCa).
We report here the revised version of this work, which successively considers the phenotype and tumor risks associated with this genotype, differential diagnoses, criteria and strategy for molecular genetic testing and recommendations for the management of affected individuals. We also discuss the phenotype and tumor risks associated with monoallelic pathogenic variants of MUTYH. PMID: 33059073 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - October 12, 2020 Category: Genetics & Stem Cells Authors: Colas C, Bonadona V, Baert-Desurmont S, Bonnet D, Coulet F, Dhooge M, Saurin JC, Remenieras A, Bignon YJ, Caron O, De Pauw A, Buisine MP, Buecher B Tags: Eur J Med Genet Source Type: research

Global retardation and hereditary spherocytosis associated with a novel deletion of chromosome 8p11.21 encompassing KAT6A and ANK1.
Abstract The loss of heterozygosity localized at chromosome segment 8p11.2 causes a contiguous gene syndrome, which mostly combined phenotype of Kallmann syndrome and hereditary spherocytosis. It has been documented that this combined phenotype is in association with both the deletion of the fibroblast growth factor receptor 1 (FGFR1) and ankyrin 1 (ANK1) genes. Here, we described a 6-year-old girl with microcephaly, global developmental delay, mental retardation, and hereditary spherocytosis, associated with a heterozygous pathogenic microdeletion of 1.9 Mb size at 8p11.21. Molecular analysis confirmed that the i...
Source: European Journal of Medical Genetics - October 12, 2020 Category: Genetics & Stem Cells Authors: Dayan W, Panjian L Tags: Eur J Med Genet Source Type: research

Expanding phenotypic and mutational spectra of mitochondrial HMG-CoA synthase deficiency.
Abstract Mitochondrial 3-hydroxy-3 methylglutaryl-CoA synthase-2 deficiency (HMGCS2D) is a rare autosomal recessive inborn error of hepatic ketogenesis, caused by mutations in HMGCS2. As its clinical and laboratory manifestations resemble many other metabolic disorders, HMGCS2D definite diagnosis presents a challenge, frequently requiring molecular tests. Only 26 patients with HMGCS2 mutations have been previously described, and this study reports the first two unrelated Thai patients, a 9-month-old male and an 8-month-old female, with HMGCS2D. During acute episodes, steatorrhea and dyslipidemia occurred, both pre...
Source: European Journal of Medical Genetics - October 9, 2020 Category: Genetics & Stem Cells Authors: Rojnueangnit K, Maneechai P, Thaweekul P, Piriyanon P, Khositseth S, Ittiwut C, Chetruengchai W, Kamolvisit W, Theerapanon T, Suphapeetiporn K, Porntaveetus T, Shotelersuk V Tags: Eur J Med Genet Source Type: research

ANO3 and early-onset dyskinetic encephalopathy.
e;nez-García M, Álvarez S, Fernández-Jaén A Abstract Mutations in the ANO3 gene have been associated with autosomal dominant craniocervical dystonia. However, little else is known about the genotype-phenotype characteristics of this disorder. Here we describe a 3 years-old girl with distal myoclonic dystonia. Whole exome sequencing in trio revealed a de novo missense ANO3 variant not previously described in international databases. A global psychomotor regression was observed once dystonia was present. Brain MRI changes paralleled these findings: whereas MRI at the age of 18 months was ...
Source: European Journal of Medical Genetics - October 9, 2020 Category: Genetics & Stem Cells Authors: Jiménez de Domingo A, Lopez-Martín S, Albert J, Jiménez de la Peña M, Tirado P, Fernández-Mayoralas DM, Fernández-Perrone AL, Calleja-Pérez B, Martínez-García M, Álvarez S, Fernández-Jaén A Tags: Eur J Med Genet Source Type: research

An unusual combination of an atypical maternally inherited novel 0.3Mb deletion in Williams-Beuren region and a de novo 22q11.21 microduplication in an infant with supravalvular aortic stenosis.
Abstract Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by supravalvular aortic stenosis (SVAS), intellectual disability, overfriendliness and dysmorphic features. It is typically caused by 1.5-1.8 Mb deletions on 7q11.23. The 22q11.21 microduplication syndrome has a variable phenotype and is frequently associated with congenital heart disease. Here we present a unique patient, carrying aberrations within both of the above syndrome regions, referred for possible diagnosis of WBS because of SVAS. The patient was a boy who died suddenly 47 days after birth, possibly due to cardiac...
Source: European Journal of Medical Genetics - October 9, 2020 Category: Genetics & Stem Cells Authors: Evangelidou P, Kousoulidou L, Salameh N, Alexandrou A, Papaevripidou I, Alexandrou IM, Ketoni A, Ioannidou C, Christophidou-Anastasiadou V, Tanteles GA, Sismani C Tags: Eur J Med Genet Source Type: research

Association analysis of FMR1 genetic variants and Primary Ovarian Insufficiency in South Indian women with a novel approach of CGG repeats classification.
Abstract Around 20-28% of FMR1gene CGG premutation (PM) carriers are at augmented risk towards an infertility related disorder, Fragile X-associated primary ovarian insufficiency (FXPOI). Except the effect of CGG repeats, reports are not available on the mechanism through which the cis-acting variations, namely, SNPs involved in POI susceptibility. Addressing the hypothesis that the FMR1 gene polymorphisms [CGG repeats, rs25731(T>A) and rs4949(A>G)] might increase their individual and combined impact in disease predisposition, we tested the genetic variants in 200 south Indian DNA samples consists of 100 pat...
Source: European Journal of Medical Genetics - October 8, 2020 Category: Genetics & Stem Cells Authors: Komaravalli PL, Rani S V, Dalal AB, Jahan P Tags: Eur J Med Genet Source Type: research

National recommendations of the French Genetics and Cancer Group - Unicancer on the modalities of multi-genes panel analyses in hereditary predispositions to tumors of the digestive tract.
Group Abstract In case of suspected hereditary predisposition to digestive cancers, next-generation sequencing can analyse simultaneously several genes associated with an increased risk of developing these tumors. Thus, "Gastro Intestinal" (GI) gene panels are commonly used in French molecular genetic laboratories. Lack of international recommendations led to disparities in the composition of these panels and in the management of patients. To harmonize practices, the Genetics and Cancer Group (GGC)-Unicancer set up a working group who carried out a review of the literature for 31 genes of interest in thi...
Source: European Journal of Medical Genetics - October 8, 2020 Category: Genetics & Stem Cells Authors: Dhooge M, Baert-Desurmont S, Corsini C, Caron O, Andrieu N, Berthet P, Bonadona V, Cohen-Haguenauer O, De Pauw A, Delnatte C, Dussart S, Lasset C, Leroux D, Maugard C, Moretta-Serra J, Popovici C, Buecher B, Colas C, Noguès C, GGC-Unicancer Group Tags: Eur J Med Genet Source Type: research

3q29 Microduplication Syndrome: Clinical and Molecular Description of Eleven New Cases.
Abstract Interstitial duplications of 3q29 have recently been described in association with a new genetic syndrome characterized by a neurodevelopmental phenotype. A total of 16 individuals with the 3q29 duplication have been reported in the literature with clinical features that include intellectual disability, language delay, epilepsy, structural brain anomalies, micro/macrocephaly, generalized obesity, ocular abnormalities, distinctive facial features, cleft palate, and musculoskeletal anomalies. In this paper, we summarize the current literature and present eleven additional cases from nine families with the 3...
Source: European Journal of Medical Genetics - October 8, 2020 Category: Genetics & Stem Cells Authors: Coyan AG, Dyer LM Tags: Eur J Med Genet Source Type: research

The p.(Cys150Tyr) variant in CSRP3 is associated with late-onset hypertrophic cardiomyopathy in heterozygous individuals.
In this study, we describe an HCM cohort with a missense variant in CSRP3 (p.Cys150Tyr) with supporting evidence for pathogenicity and a description of the associated phenotype. METHODS: CSRP3 was sequenced in 6,456 index cases with a diagnosis of HCM and in 5,012 probands with other cardiomyopathies. In addition, 3,372 index cases with hereditary cardiovascular disorders other than cardiomyopathies (mainly channelopathies and aortopathies) were used as controls. RESULTS: The p.(Cys150Tyr) variant was identified in 11 unrelated individuals of the 6,456 HCM probands, and it was not identified in patients with othe...
Source: European Journal of Medical Genetics - October 6, 2020 Category: Genetics & Stem Cells Authors: Salazar-Mendiguchía J, Barriales-Villa R, Lopes LR, Ochoa JP, Rodríguez-Vilela A, Palomino-Doza J, Larrañaga-Moreira JM, Cicerchia M, Cárdenas-Reyes I, García-Giustiniani D, Brögger N, Fernández G, García S, L S, P V, Ortiz-Genga M, Elliott PM, Mo Tags: Eur J Med Genet Source Type: research

Molecular characterization of Temple syndrome families with 14q32 epimutations.
We present 16 TS14 patients with molecular alterations affecting the MEG3:TSS-DMR, comprising seven patients (43.8%) with LOM, six carriers with upd(14)mat (37.5%), and three cases (18.8%) with a deletion affecting the paternal MEG3:TSS-DMR. We did not find any evidence for MLID in the LOM group, including two cases in which different tissues were available. Whole exome sequencing (WES) in the MEG3:TSS-DMR LOM patients and their parents (Trio WES) did not reveal an obvious pathogenic variant which might cause aberrant methylation at imprinted loci. By summarizing our data with those from the literature, we could show that ...
Source: European Journal of Medical Genetics - September 29, 2020 Category: Genetics & Stem Cells Authors: Brück J, Begemann M, Dey D, Elbracht M, Eggermann T Tags: Eur J Med Genet Source Type: research

Which types of conditions should be included in reproductive genetic carrier screening?: Views of parents of children with a genetic condition.
This study sought to identify which types of conditions parents of children with a genetic condition believe should be included in carrier screening. Participants (n=150) were recruited through Melbourne paediatric hospital outpatient clinics, the Genetic Support Network of Victoria (GSNV) and a databank of children with hearing loss. This study found that the majority of participants support offering carrier screening for: neuromuscular conditions (n=128/134, 95.5%), early fatal neurodegenerative conditions (n=130/141, 92.2%), chronic multi-system disorders (n=124/135, 91.9%), conditions which cause intellectual disabilit...
Source: European Journal of Medical Genetics - September 28, 2020 Category: Genetics & Stem Cells Authors: Thomas LA, Lewis S, Massie J, Kirk EP, Archibald AD, Barlow-Stewart K, Boardman FK, Halliday J, McClaren B, Delatycki MB Tags: Eur J Med Genet Source Type: research

IFT144 and mild retinitis pigmentosa in Mainzer-Saldino syndrome: a new association.
In conclusion, IFT144 genetic study may be involved in MSS and thus must be considered for diagnosis. Mild ophthalmic symptomatology despite early onset retinitis pigmentosa in the context of MSS has been found in this case caused by IFT144 mutation. PMID: 33002628 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - September 27, 2020 Category: Genetics & Stem Cells Authors: Montolío-Marzo S, Català-Mora J, Madrid-Aris Á, Armstrong J, Diaz-Carcajosa J, Carreras E Tags: Eur J Med Genet Source Type: research

Associations between cognitive performance and the rehabilitation, medical care and social support provided to French children with Prader-Willi syndrome.
In conclusion, children and adolescents with PWS generally received appropriate care. Though there have been considerable improvements in the management of children with PWS, reference centres should continue reinforcing the coordination of multidisciplinary supervision. PMID: 32998064 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - September 26, 2020 Category: Genetics & Stem Cells Authors: Roux-Levy PH, Bournez M, Masurel A, Jean N, Chancenotte S, Bordes M, Debomy F, Minot D, Schmitt E, Vinault S, Gautier E, Lacombe D, Odent S, Mikaty M, Manouvrier S, Ghoumid J, Geneviève D, Lehman N, Philip N, Edery P, Cornaton J, Gallard J, Héron D, Ras Tags: Eur J Med Genet Source Type: research

Phenotypic spectrum of SHANK2-related neurodevelopmental disorder.
Abstract SHANK2 code a scaffolding protein located at the postsynaptic membrane of glutamatergic neurons. To date, only nine patients were reported with a SHANK2-variation or microdeletion. Molecular anomalies were identified through screening of large cohorts of patients, but only poor patient clinical descriptions were available. However, this information is crucial for patient care. Here, we describe two additional unrelated patients carrying a SHANK2 de novo variant, improving the delineation of the condition. Phenotypic analysis of these 11 patients identified as major features of the condition: mild to moder...
Source: European Journal of Medical Genetics - September 24, 2020 Category: Genetics & Stem Cells Authors: Caumes R, Smol T, Thuillier C, Balerdi M, Lestienne-Roche C, Manouvrier-Hanu S, Ghoumid J Tags: Eur J Med Genet Source Type: research

Dual diagnosis of osteogenesis imperfecta (OI) and short stature and advanced bone age with or without early-onset osteoarthritis and/or osteochondritis dissecans (SSOAOD) reveals a cumulative effect on stature caused by mutations in COL1A1 and ACAN genes.
Abstract Short stature is a feature when a person's height is more than 2 SDS below the corresponding mean height for a given age, gender, and population. It can be influenced by many factors essential to growth plate. Here we report a three-generation family with 13 patients affected by osteogenesis imperfecta (OI) type I, short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (SSOAOD) or both. Panel sequencing of the proband revealed mutations in two extracellular matrix related genes: COL1A1 and ACAN. When comparing the quantitative trait, height within ...
Source: European Journal of Medical Genetics - September 23, 2020 Category: Genetics & Stem Cells Authors: Ye X, Fang D, He Y, Yan H, Qiu W, Sun Y Tags: Eur J Med Genet Source Type: research

Methionine Adenosyltransferase I/III Deficiency: Long-Term Follow-up and Treatment of 3 Adult Siblings.
Abstract Methionine adenosyltransferase I/III deficiency, also known as Mudd's disease, is a rare inborn error of methionine metabolism. Because pathophysiological mechanisms of the disease remain poorly understood, the consequences of this disorder and the need for medical management remain uncertain; likewise, the effect of metabolic interventions on clinical outcomes in Mudd's disease is largely unknown due to a relative lack of published longitudinal clinical data. There are few reports of adults in the medical literature affected with this disease. Clinical symptoms of reported adults range from asymptomatic ...
Source: European Journal of Medical Genetics - September 23, 2020 Category: Genetics & Stem Cells Authors: Bannick A, Chase S, Miner A, Seeterlin M, Conway RL Tags: Eur J Med Genet Source Type: research

A novel pathogenic variant in DYNC1H1 causes various upper and lower motor neuron anomalies.
CONCLUSION: Our study demonstrates the wide clinical variability associated with a single disease causing variant in DYNC1H1 gene and this variant demonstrated a high penetrance within this large family. PMID: 32947049 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - September 14, 2020 Category: Genetics & Stem Cells Authors: Viollet LM, Swoboda KJ, Mao R, Best H, Ha Y, Toutain A, Guyant-Marechal L, Laroche-Raynaud C, Ghorab K, Barthez MA, Pedespan JM, Hernandorena X, Lia AS, Deleuze JF, Masson C, Nelson I, Nectoux J, Si Y Tags: Eur J Med Genet Source Type: research

Impact of COVID-19 pandemic on patients with rare disease in Hong Kong.
This study examines the impact of the COVID-19 pandemic on 272 rare disease patients with 89 distinct rare diseases in Hong Kong using a cross-sectional online survey between April 10 and April 29, 2020 from the patient and caregiver perspective. The pandemic has impacted patient's health status in 46%, service use patterns in 71%, mental health in 79%, daily living in 82%, social life in 92%, and financial status in 81% of patients. Patient's health status, medical and rehabilitation, and mental health were more impacted by the COVID-19 pandemic in the group of patients with any level of dependency according to the Barthe...
Source: European Journal of Medical Genetics - September 11, 2020 Category: Genetics & Stem Cells Authors: Chung CC, Wong WH, Fung JL, Hong Kong RD, Chung BH Tags: Eur J Med Genet Source Type: research

Spondylo-epiphyseal dysplasia in two sibs due to a homozygous splicing variant in COL2A1.
Abstract Type 2 collagenopathies encompass a large group of chondrodysplasias ranging from the perinatally lethal achondrogenesis type 2 and hypochondrogenesis at the severe end of the spectrum to early-onset osteoarthritis with normal stature at the milder end of the spectrum. With the exception of a few reported cases, these dysplasias are predominantly caused by heterozygous variants in the COL2A1 gene and hence show an autosomal dominant inheritance pattern. Here we report on two siblings, originating from a consanguineous family, who presented with disproportionate short stature, ocular abnormalities, cleft p...
Source: European Journal of Medical Genetics - September 3, 2020 Category: Genetics & Stem Cells Authors: Al-Sannaa NA, Hoornaert KP, Van Laer L, Al-Abdulwahed HY, Mortier G Tags: Eur J Med Genet Source Type: research

Severe gastrointestinal symptoms caused by a novel DDX3X variant.
This report expands the phenotype caused by DDX3X variants and reveals an important clinical aspect for patients and medical staff. PMID: 32896648 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - September 3, 2020 Category: Genetics & Stem Cells Authors: Okano S, Miyamoto A, Makita Y, Taketazu G, Kimura K, Fukuda I, Tanaka H, Yanagi K, Kaname T Tags: Eur J Med Genet Source Type: research

Early diagnosis of WT1 nephropathy and follow up in a Chinese multicenter cohort.
CONCLUSION: Screening for WT1 mutations should be performed in children with Wilms' tumor, proteinuria/SRNS or CKD. Early diagnosis of WT1 nephropathy through clinical and genetic findings is warranted. PMID: 32891756 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - September 2, 2020 Category: Genetics & Stem Cells Authors: Sun S, Xu L, Bi Y, Wang J, Zhang Z, Tang X, Cao Q, Zhai Y, Chen J, Fang X, Liu J, Fang Y, Xiang T, Qian Y, Wu B, Wang H, Zhou W, Shen J, Dong K, Liu X, Zheng B, Zhang A, Wang X, Wu Y, Ma D, Shen Q, Rao J, Xu H Tags: Eur J Med Genet Source Type: research

Myoclonic tremor status as a presenting symptom of adenylosuccinate lyase deficiency.
In conclusion, myoclonic tremor status expands the spectrum of movement disorders seen in adenylosuccinate lyase deficiency. PMID: 32890691 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - September 1, 2020 Category: Genetics & Stem Cells Authors: Andelman-Gur MM, Saitsu H, Matsumoto N, Spiegel R, Yosovich K, Lev D, Lerman-Sagie T, Blumkin L Tags: Eur J Med Genet Source Type: research

TSC1 intragenic deletion transmitted from a mosaic father to two siblings with cardiac rhabdomyomas: Identification of two aberrant transcripts.
Abstract Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder characterized by non-cancerous tumors in multiple organs including the brain, kidney, lung, heart, and skin. We encountered a Japanese family consisting of two siblings (a four-year-old boy and a one-year-old girl) with multiple cardiac rhabdomyomas conveying a high risk of TSC and apparently unaffected sibling (a two-year-old girl) and parents. Whole exome sequencing and application of Integrative Genomic Viewer revealed an identical intragenic TSC1 deletion with the breakpoints on intron 15 and exon 19 in the affected siblings, but n...
Source: European Journal of Medical Genetics - August 31, 2020 Category: Genetics & Stem Cells Authors: Uchiyama H, Masunaga Y, Ishikawa T, Fukuoka T, Fukami M, Saitsu H, Ogat T Tags: Eur J Med Genet Source Type: research

A severe case of status dystonicus caused by a de novo KMT2B missense mutation.
Abstract Here, we present the case of a 15-year-old Japanese girl with Dystonia 28, childhood-onset; DYT28 (MIM#606834) showing early-onset generalized progressive dystonia and status dystonicus. The patient was genetically undiagnosed and had not responded to various medications. By trio-based whole exome sequencing and in silico analyses, we identified a de novo heterozygous variant of KMT2B: NM_014727.2: c.7828C > T, p.(Arg2610Cys). Globus pallidus internus deep brain stimulation (GPi-DBS) therapy was considered; however, the therapy could not be performed due to the patient's poor nutritional status and...
Source: European Journal of Medical Genetics - August 29, 2020 Category: Genetics & Stem Cells Authors: Nakamura S, Chinen Y, Satou K, Tokashiki T, Kumada S, Yanagi K, Kaname T, Naritomi K, Nakanishi K Tags: Eur J Med Genet Source Type: research

Follow-up of two adult brothers with homozygous CEP57 pathogenic variants expands the phenotype of Mosaic Variegated Aneuploidy Syndrome.
This report expands the phenotypical spectrum associated with CEP57 and highlights the interest of blood karyotype in patients presenting with short stature and microcephaly. PMID: 32861809 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - August 26, 2020 Category: Genetics & Stem Cells Authors: Dery T, Chatron N, Alqahtani A, Pugeat M, Till M, Edery P, Sanlaville D, Schluth-Bolard C, Nicolino M, Lesca G, Putoux A Tags: Eur J Med Genet Source Type: research

Paroxysmal and non-paroxysmal dystonia in 3 patients with biallelic ECHS1 variants: Expanding the neurological spectrum and therapeutic approaches.
CONCLUSIONS: In line with literature, our findings corroborate that the pathogenic ECHS1 variant c.518C > T (p.Ala173Val) is associated with milder phenotypes characterized by paroxysmal and non-paroxysmal dystonia. Because of the potentially treatable defect, especially in milder affected patients, it is important to consider SCEH deficiency not only in patients with Leigh-like syndrome but also in patients with paroxysmal dystonia and normal neurological findings between episodes. PMID: 32858208 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - August 24, 2020 Category: Genetics & Stem Cells Authors: Illsinger S, Korenke GC, Boesch S, Nocker M, Karall D, Nuoffer JM, Laugwitz L, Mayr JA, Scholl-Bürgi S, Freisinger P, Kowald T, Kölker S, Prokisch H, Haack TB Tags: Eur J Med Genet Source Type: research

Excess of RALGAPB de novo variants in neurodevelopmental disorders.
Abstract Autism spectrum disorder is a neurodevelopmental disorder (NDD) with complex genetic architecture marked primarily by social and communication impairments along with deficits in restrictive and repetitive behaviors. Due to the complex nature and genetic heterogeneity of the disease, genotype and phenotype correlation remains challenging. Prior studies have implicated RALGAPB as a candidate gene for ASD, but stringent analysis is required to determine the pathogenicity. By targeted sequencing, we identified a new de novo RALGAPB missense variant (c.1238C  >  T; p. (Thr413Met) in an ASD family. B...
Source: European Journal of Medical Genetics - August 23, 2020 Category: Genetics & Stem Cells Authors: Shah AA, Zhang G, Li K, Chenbin L, Kanhar AA, Wang M, Quan Y, Wu H, Shen L, Khan R, Guodong C, Ou J, Hu Z, Xia K, Guo H Tags: Eur J Med Genet Source Type: research

Young people's understanding, attitudes and involvement in decision-making about genome sequencing for rare diseases: A qualitative study with participants in the UK 100,000 genomes project.
Abstract Genome sequencing (GS) will have a profound impact on the diagnosis of rare and inherited diseases in children and young people. We conducted 27 semi-structured interviews with young people aged 11-19 having GS through the UK 100,000 Genomes Project. Participants demonstrated an understanding of the role and function of genes and DNA, however the terms 'genome' and 'genome sequencing' were less well understood. Participants were primarily motivated to take part to get a diagnosis or identify the gene causing their condition. The majority of participants understood they might not receive a diagnostic resul...
Source: European Journal of Medical Genetics - August 20, 2020 Category: Genetics & Stem Cells Authors: Lewis C, Hammond J, Hill M, Searle B, Hunter A, Patch C, Chitty LS, Sanderson SC Tags: Eur J Med Genet Source Type: research

Two new families with enamel renal syndrome: A novel FAM20A gene mutation and review of literature.
Abstract Enamel renal syndrome (ERS) or so-called amelogenesis imperfecta type IG is a very rare disorder characterized by the triad of amelogenesis imperfecta, gingival enlargement and nephrocalcinosis. It is caused by biallelic mutations in the FAM20A gene. Herein, we report two unrelated patients with ERS. Our patients presented with the characteristic features of the syndrome, and amelogenesis imperfecta and gingival hyperplasia were the main complaint. Strikingly, they both had long face, thick lips, notched upper central incisors, and thick alveolar ridge which have never been reported before in patients wit...
Source: European Journal of Medical Genetics - August 20, 2020 Category: Genetics & Stem Cells Authors: Hassib NF, Shoeib MA, ElSadek HA, Wali ME, Mostafa MI, Abdel-Hamid MS Tags: Eur J Med Genet Source Type: research

Sedaghatian-type spondylometaphyseal dysplasia: Whole exome sequencing in neonatal dry blood spots enabled identification of a novel variant in GPX4.
This report underscores the importance of DBS WES in identifying the genes and mutations causing devastating rare diseases. Obtaining critical samples from a dying patient is crucial for enabling genetic diagnosis. PMID: 32827718 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - August 18, 2020 Category: Genetics & Stem Cells Authors: Fedida A, Ben Harouch S, Kalfon L, Abunassar Z, Omari H, Mandel H, Falik-Zaccai TC Tags: Eur J Med Genet Source Type: research

Neurofibromatosis type 2 in Phelan-McDermid syndrome: Institutional experience and review of the literature.
Abstract Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by rearrangements on chromosome 22q13.3 or sequence variants in SHANK3. Individuals with PMS caused by a 22q terminal deletion and a ring chromosome are at increased risk for Neurofibromatosis type 2 (NF2). However, the prevalence of NF2 in individuals with PMS and a r (22) is unknown. Individuals with PMS and a r (22) chromosome evaluated at the Greenwood Genetic Center (GGC) or by international collaborators, or identified through the PMS International Registry (PMSIR) were contacted and participated in a clinical questionnaire....
Source: European Journal of Medical Genetics - August 17, 2020 Category: Genetics & Stem Cells Authors: Ziats CA, Jain L, McLarney B, Vandenboom E, DuPont BR, Rogers C, Sarasua S, Nevado J, Cordisco EL, Phelan K, Boccuto L Tags: Eur J Med Genet Source Type: research

FLVCR1-related disease as a rare cause of retinitis pigmentosa and hereditary sensory autonomic neuropathy.
In this report we highlight the association of retinitis pigmentosa with hypomyelinating sensory-autonomic neuropathy, which could be underdiagnosed due to variable severity. To summarize, the phenotypic heterogeneity of FLVCR1 variants is broad and should include retinitis pigmentosa along with range of neurological features. PMID: 32822874 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - August 17, 2020 Category: Genetics & Stem Cells Authors: Grudzinska Pechhacker MK, Yoon G, Hazrati LN, Maynes J, MacDonald H, Tavares E, Vincent A, Heon E Tags: Eur J Med Genet Source Type: research

Altered level of plasma exosomes in patients with gaucher disease.
Abstract Mutations in the glucocerebrosidase gene (GBA) cause Gaucher disease (GD), the lysosomal storage disorder (LSD), and are the most common genetic risk factor of Parkinson's disease (PD). Lysosome functionality plays a critical role for secretion of extracellular vesicles (EVs) and their content. Here we compared EVs from the blood plasma of 8 GD patients and 8 controls in terms of amounts, size distribution, and composition of their protein cargo. EVs were isolated via sequential centrifugation and characterized by сryo-electron microscopy (cryo-EM), nanoparticle tracking analysis (NTA), and dynamic light...
Source: European Journal of Medical Genetics - August 17, 2020 Category: Genetics & Stem Cells Authors: Tatiana S, Stanislav N, Darya K, Luiza G, Konstantin S, Sergey L, Elena V, Galina S, Nikolai V, Arthur K, Elena Z, Roman K, Tatiana U, Alexander S, Ekaterina Z, Anton E, Sofya P Tags: Eur J Med Genet Source Type: research

A novel homozygous KY variant causing a complex neurological disorder.
Abstract Mutations in the gene kyphoscoliosis peptidase (KY) are known to cause myofibrillar myopathy-7 and hereditary spastic paraplegia. We investigated the genetic cause of a complex neurological phenotype in a consanguineous Pakistani family with four affected members, manifesting lower limb spasticity and weakness, toe walking, pes equinovarus, and a speech disorder. Genome-wide linkage analysis with microsatellite markers delineated chromosome 3q22.2-q24 harboring the disease gene. Whole exome sequencing was performed for two subjects, identifying a homozygous 14-bp frameshift deletion NM_178554.6:c.842_855d...
Source: European Journal of Medical Genetics - August 16, 2020 Category: Genetics & Stem Cells Authors: Arif B, Rasheed A, Kumar KR, Fatima A, Abbas G, Wohler E, Sobriera N, Lohmann K, Baylor-Hopkins Center for Mendelian Genomics Tags: Eur J Med Genet Source Type: research

Targeted re-sequencing in pediatric and perinatal stroke.
Abstract Pediatric and perinatal stroke can present as an early symptom in undiagnosed syndromes characterized by simple Mendelian inheritance. In order to diagnose those patients affected with a monogenic disorder in which an arterial cerebrovascular event or arteriopathy may have preceded any other specific symptom, we aimed to establish and validate a targeted gene panel, and to determine its diagnostic yield and clinical utility. To this end, thirty-eight patients were selected with heterogeneous cryptogenic stroke phenotypes, mostly including multiple and recurrent ischemic or hemorrhagic arterial strokes and...
Source: European Journal of Medical Genetics - August 16, 2020 Category: Genetics & Stem Cells Authors: Grossi A, Severino M, Rusmini M, Tortora D, Ramenghi LA, Cama A, Rossi A, Di Rocco M, Ceccherini I, Bertamino M, Gaslini Stroke Study Group Tags: Eur J Med Genet Source Type: research

A 34-year-old Japanese patient exhibiting NBAS deficiency with a novel mutation and extended phenotypic variation.
Abstract Biallelic neuroblastoma amplified sequence (NBAS) gene mutations have recently been identified to cause a reduction in its protein expression and a broad phenotypic spectrum, from isolated short stature, optic nerve atrophy, and Pelger-Huët anomaly (SOPH) syndrome or infantile liver failure syndrome 2 to a combined, multi-systemic disease including skeletal dysplasia and immunological and neurological abnormalities. Herein, we report a 34-year-old patient with a range of phenotypes for NBAS deficiency due to compound heterozygous variants; one is a SOPH-specific variant, p.Arg1914His, and the other ...
Source: European Journal of Medical Genetics - August 13, 2020 Category: Genetics & Stem Cells Authors: Suzuki S, Kokumai T, Furuya A, Nagamori T, Matsuo K, Ueda O, Mukai T, Ito Y, Yano K, Fujieda K, Okuno A, Tanahashi Y, Azuma H Tags: Eur J Med Genet Source Type: research

Disclosing genetic information to family members without consent: Five Australian case studies.
Abstract Genetic risk information is relevant to individual patients and also their blood relatives. Health practitioners (HPs) routinely advise patients of the importance of sharing genetic information with family members, especially for clinically actionable conditions where prevention is possible. However, some patients refuse to share genetic results with at-risk relatives, and HPs must choose whether to use or disclose genetic information without consent. This requires an understanding of their legal and ethical obligations, which research shows many HPs do not have. A recent UK case held that HPs have a duty...
Source: European Journal of Medical Genetics - August 13, 2020 Category: Genetics & Stem Cells Authors: Tiller J, Bilkey G, Macintosh R, O'Sullivan S, Groube S, Palover M, Pachter N, Rothstein M, Lacaze P, Otlowski M Tags: Eur J Med Genet Source Type: research

X-linked myotubular myopathy mimics hereditary spastic paraplegia in two female manifesting carriers of pathogenic MTM1 variant.
This report suggests association between spastic paraplegia and pathogenic MTM1 variants expanding the phenotypic spectrum potentially associated with XLMTM, but the possible association needs to be confirmed by additional cases. PMID: 32805447 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - August 13, 2020 Category: Genetics & Stem Cells Authors: Kraatari M, Tuominen H, Tuupanen S, Haapaniemi T, Moilanen J, Rahikkala E Tags: Eur J Med Genet Source Type: research

Compassionate use of everolimus for refractory epilepsy in a patient with MTOR mosaic mutation.
We report here the case of a patient, with an MTOR mosaic gain-of-function variant (p.Glu2419Lys) in the DNA of 41% skin cells, who received compassionate off-label treatment with everolimus for refractory epilepsy. This 12-year-old-girl presented with psychomotor regression, intractable seizures, hypopigmentation along Blaschko's lines (hypomelanosis of Ito), asymmetric regional body overgrowth, and ocular anomalies, as well as left cerebral hemispheric hypertrophy with some focal underlying migration disorders. In response to the patient's increasingly frequent epileptic seizures, everolimus was initiated (after approval...
Source: European Journal of Medical Genetics - August 13, 2020 Category: Genetics & Stem Cells Authors: Hadouiri N, Darmency V, Guibaud L, Arzimanoglou A, Sorlin A, Carmignac V, Rivière JB, Huet F, Luu M, Bardou M, Thauvin-Robinet C, Vabres P, Faivre L Tags: Eur J Med Genet Source Type: research

Integration of genetic counsellors in genomic testing triage: Outcomes of a Genomic Consultation Service in British Columbia, Canada.
CONCLUSION: The GCS provided an effective model in which physicians can interface with genetic specialists, including genetic counsellors, to facilitate appropriate genomic test selection. PMID: 32798762 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - August 12, 2020 Category: Genetics & Stem Cells Authors: Cook CB, Dragojlovic N, Siemens A, Adam S, du Souich C, van Karnebeek C, Lehman A, Nelson TN, Friedman J, CAUSES Study, GenCOUNSEL Study Tags: Eur J Med Genet Source Type: research

Pathophysiology of premature aging characteristics in Mendelian progeroid disorders.
Abstract Aging is a physiological process that is in part genetically determined. Some of the signs and symptoms of aging also occur prematurely in Mendelian disorders. Such disorders are excellent sources of information of underlying mechanisms for these components of aging, and studying these may allow detection of pathways that have not yet considered in detail in physiological aging. Here I define the clinical characteristics that constitute aging and propose that at least 40% of aging signs and symptoms should be present before an entity should be tagged as progeroid. A literature search using these character...
Source: European Journal of Medical Genetics - August 9, 2020 Category: Genetics & Stem Cells Authors: Hennekam RCM Tags: Eur J Med Genet Source Type: research

A patient with atypical presentation of chronic hepatosteatosis and developmental delay harboring a novel variant in the CPT1A gene.
We present an atypical case of an 8-year-old male with CPT1A deficiency, developmental delay, autistic spectrum disorder and liver cirrhosis. His newborn screening test suggested CPT1A deficiency but confirmatory biochemical testing was not conclusive. The patient never experienced a metabolic crisis. At age six, hepatomegaly was detected. Further investigations showed transaminitis, hepatosteatosis and cirrhosis. Repeat acylcarnitine profile and total/free carnitine were consistent with CPT1A deficiency. The CPTI enzyme activity was 18% of normal on fibroblast enzyme assay. A novel homozygous variant in the CPT1A gene, c....
Source: European Journal of Medical Genetics - August 7, 2020 Category: Genetics & Stem Cells Authors: Boonsimma P, Crosby K, Mohan P, Puscasiu E, Tanpaiboon P Tags: Eur J Med Genet Source Type: research

PRPS1 loss-of-function variants, from isolated hearing loss to severe congenital encephalopathy: New cases and literature review.
We describe two sporadic and two familial cases with loss-of-function variants in PRPS1, which is located on the X chromosome and encodes phosphoribosyl pyrophosphate synthetase 1 (PRS-1). We illustrate the clinical variability associated with decreased PRS-1 activity, ranging from mild isolated hearing loss to severe encephalopathy. One of the variants we identified has already been reported with a phenotype similar to our patient's, whereas the other three were unknown. The clinical and biochemical information we provide will hopefully contribute to gain insight into the correlation between genotype and phenotype of this...
Source: European Journal of Medical Genetics - August 7, 2020 Category: Genetics & Stem Cells Authors: Mercati O, Abi Warde MT, Lina-Granade G, Rio M, Heide S, de Lonlay P, Ceballos-Picot I, Robert MP, Couloigner V, Beltrand J, Boddaert N, Rodriguez D, Rubinato E, Lapierre JM, Merlette C, Sanquer S, Rötig A, Prokisch H, Lyonnet S, Loundon N, Kaplan J, Bon Tags: Eur J Med Genet Source Type: research

Glutaric aciduria type 1: Genetic and phenotypic spectrum in 53 patients.
CONCLUSION: This study is the first comprehensive research from Turkey that provides information about disease-causing variants in the GCDH gene. The identification of common variants and hot spot regions of the GCDH gene is important for genetic counselling and the prenatal diagnosis of Turkish patients with GA1. PMID: 32777384 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - August 6, 2020 Category: Genetics & Stem Cells Authors: Gürbüz BB, Yılmaz DY, Coşkun T, Tokatlı A, Dursun A, Sivri HS Tags: Eur J Med Genet Source Type: research

ISL1 loss-of-function variation causes familial atrial fibrillation.
Abstract Atrial fibrillation (AF) represents the most frequent form of sustained cardiac rhythm disturbance, affecting approximately 1% of the general population worldwide, and confers a substantially enhanced risk of cerebral stroke, heart failure, and death. Increasing epidemiological studies have clearly demonstrated a strong genetic basis for AF, and variants in a wide range of genes, including those coding for ion channels, gap junction channels, cardiac structural proteins and transcription factors, have been identified to underlie AF. Nevertheless, the genetic pathogenesis of AF is complex and still far fro...
Source: European Journal of Medical Genetics - August 5, 2020 Category: Genetics & Stem Cells Authors: Wu SH, Wang XH, Xu YJ, Gu JN, Yang CX, Qiao Q, Guo XJ, Guo YH, Qiu XB, Jiang WF, Yang YQ Tags: Eur J Med Genet Source Type: research

Genotype-phenotype correlations of UBA2 mutations in patients with ectrodactyly.
We report a boy with a de novo frameshift mutation in UBA2 (c.612delA (p.(Glu205Lysfs*63)), presenting with ectrodactyly of the feet associated with learning difficulties and minor physical anomalies. We review genotype-phenotype correlations in patients with chromosomal 19q13.11 microdeletions compared to those with intragenic UBA2 mutations. PMID: 32758660 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - August 2, 2020 Category: Genetics & Stem Cells Authors: Aerden M, Bauters M, Van Den Bogaert K, Vermeesch JR, Holvoet M, Frank P, Devriendt K Tags: Eur J Med Genet Source Type: research

Clinical and genetic findings in Hungarian pediatric patients carrying chromosome 16p copy number variants and a review of the literature.
We present the phenotypic and genotypic results of our patients and discuss our findings in relation to the available literature. PMID: 32758661 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - August 2, 2020 Category: Genetics & Stem Cells Authors: Lengyel A, Pinti É, Pikó H, Jávorszky E, David D, Tihanyi M, Gönczi É, Kiss E, Tóth Z, Tory K, Fekete G, Haltrich I Tags: Eur J Med Genet Source Type: research

UFSP2-related spondyloepimetaphyseal dysplasia: A confirmatory report.
In this report, we describe a boy with spondyloepimetaphyseal dysplasia due to a novel mutation exon 11: c.1283A  >  G (leading to p. H428R) of the UFSP2 gene. This is the second report to describe children with SEMDs associated with an UFSP2 variant. However, it is the first to describe a UFSP2 gene mutation exon 11: c.1283A  >  G (leading to p. H428R). Our findings of a novel heterozygous mutation of UFSP2 gene add to the list of 2 reported heterozygous mutations of UFSP2 which led to hereditary osteopathy. PMID: 32755715 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - August 1, 2020 Category: Genetics & Stem Cells Authors: Zhang G, Tang S, Wang H, Pan H, Zhang W, Huang Y, Kong J, Wang Y, Gu J, Wang Y Tags: Eur J Med Genet Source Type: research