Publications by authors named "Sally Ann Lynch"

94 Publications

HK1 haemolytic anaemia in association with a neurological phenotype and co-existing CEP290 Meckel-Gruber in a Romani family.

Clin Genet 2021 Sep 16. Epub 2021 Sep 16.

Clinical Genetics, CHI Crumlin, Dublin, Ireland.

HK1 deficient Haemolytic Anaemia in association with a Neurological Phenotype & co-existing Meckel-Gruber due to CEP290 in a Romani family.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.14058DOI Listing
September 2021

De novo missense variants in FBXO11 alter its protein expression and subcellular localization.

Hum Mol Genet 2021 Sep 9. Epub 2021 Sep 9.

Research Centre for Medical Genetics, Moscow, 115522, Russia.

Recently, we and others identified de novo FBXO11 variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddab265DOI Listing
September 2021

Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3.

Am J Med Genet A 2021 Aug 26. Epub 2021 Aug 26.

Neurology Clinic, Department of Medicine, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy.

The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.62465DOI Listing
August 2021

Fatal fetal abnormality Irish live-born survival-an observational study.

J Community Genet 2021 Jul 2. Epub 2021 Jul 2.

National Rare Disease Office, Mater Misericordiae University Hospital, Dublin, Republic of Ireland.

The aim of the study was to provide accurate information regarding live-born infant survival after diagnosis of fatal fetal anomaly (FFA) to aid decision-making in respect of pregnancy management, and to ascertain the natural history of live-born infants with FFAs via a retrospective analysis of death records (2006-2018), from the National Paediatric Mortality Registry (source Central Statistics Office 2019). Diagnoses and survival times were ascertained from narrative records with further ascertainment and reconciliation of trisomies 13 and 18 cases by review of cytogenetic test records, the National Death Events Register and National Perinatal Epidemiology Centre data. During the study period, termination of pregnancy was not permitted under the Irish Constitution. Patients are live-born babies with fatal fetal anomalies whose deaths were registered in the Republic of Ireland. The main outcome measure was construction of anomaly-specific survival curves, or survival time range and median for those anomalies with rare occurrence. Survival curves for anencephaly, bilateral renal agenesis, thanatophoric dysplasia, trisomy 13, and trisomy 18 show that 90% (n = 95), 93% (n = 60), 100% (n = 14), 37% (n = 92) and 33% (n = 162), respectively, were deceased by 24 h and 98%, 100%, 100%, 73%, and 53%, respectively, by 1 week post-delivery. Survival time range and median were calculated for triploidy (3.5 h-20 days; 10.5 days), whose occurrence was rare. Anhydramnios, craniorachischisis, hydranencephaly and severe hydrocephalus were extremely rare and all deaths were neonatal deaths. Our results provide 13 years of national natural history data of live birth FFA survival. This provides objective information to aid obstetric counselling of couples upon diagnosis of an FFA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12687-021-00534-3DOI Listing
July 2021

Delineating the Smith-Kingsmore syndrome phenotype: Investigation of 16 patients with the MTOR c.5395G > A p.(Glu1799Lys) missense variant.

Am J Med Genet A 2021 08 25;185(8):2445-2454. Epub 2021 May 25.

St George's University of London, London, UK.

Smith-Kingsmore Syndrome (SKS) is a rare genetic syndrome associated with megalencephaly, a variable intellectual disability, autism spectrum disorder, and MTOR gain of function variants. Only 30 patients with MTOR missense variants are published, including 14 (47%) with the MTOR c.5395G>A p.(Glu1799Lys) variant. Limited phenotypic data impacts the quality of information delivered to families and the robustness of interpretation of novel MTOR missense variation. This study aims to improve our understanding of the SKS phenotype through the investigation of 16 further patients with the MTOR c.5395G>A p.(Glu1799Lys) variant. Through the careful phenotypic evaluation of these 16 patients and integration with data from 14 previously reported patients, we have defined major (100% patients) and frequent (>15%) SKS clinical characteristics and, using these data, proposed guidance for evidence-based management. In addition, in the absence of functional studies, we suggest that the combination of the SKS major clinical features of megalencephaly (where the head circumference is at least 3SD) and an intellectual disability with a de novo MTOR missense variant (absent from population databases) should be considered diagnostic for SKS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.62350DOI Listing
August 2021

ANKRD11 variants: KBG syndrome and beyond.

Clin Genet 2021 08 14;100(2):187-200. Epub 2021 May 14.

Centro Fondazione Mariani per il Bambino Fragile ASST-Lariana Sant'Anna Hospital, Department of Pediatrics, San Fermo della Battaglia (Como), Italy.

Mutations affecting the transcriptional regulator Ankyrin Repeat Domain 11 (ANKRD11) are mainly associated with the multisystem developmental disorder known as KBG syndrome, but have also been identified in individuals with Cornelia de Lange syndrome (CdLS) and other developmental disorders caused by variants affecting different chromatin regulators. The extensive functional overlap of these proteins results in shared phenotypical features, which complicate the assessment of the clinical diagnosis. Additionally, re-evaluation of individuals at a later age occasionally reveals that the initial phenotype has evolved toward clinical features more reminiscent of a developmental disorder different from the one that was initially diagnosed. For this reason, variants in ANKRD11 can be ascribed to a broader class of disorders that fall within the category of the so-called chromatinopathies. In this work, we report on the clinical characterization of 23 individuals with variants in ANKRD11. The subjects present primarily with developmental delay, intellectual disability and dysmorphic features, and all but two received an initial clinical diagnosis of either KBG syndrome or CdLS. The number and the severity of the clinical signs are overlapping but variable and result in a broad spectrum of phenotypes, which could be partially accounted for by the presence of additional molecular diagnoses and distinct pathogenic mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13977DOI Listing
August 2021

The genetic landscape of polycystic kidney disease in Ireland.

Eur J Hum Genet 2021 May 16;29(5):827-838. Epub 2021 Jan 16.

School of Pharmacy and Biomolecular Science, Royal College of Surgeons in Ireland, Dublin, Ireland.

Polycystic kidney diseases (PKDs) comprise the most common Mendelian forms of renal disease. It is characterised by the development of fluid-filled renal cysts, causing progressive loss of kidney function, culminating in the need for renal replacement therapy or kidney transplant. Ireland represents a valuable region for the genetic study of PKD, as family sizes are traditionally large and the population relatively homogenous. Studying a cohort of 169 patients, we describe the genetic landscape of PKD in Ireland for the first time, compare the clinical features of patients with and without a molecular diagnosis and correlate disease severity with autosomal dominant pathogenic variant type. Using a combination of molecular genetic tools, including targeted next-generation sequencing, we report diagnostic rates of 71-83% in Irish PKD patients, depending on which variant classification guidelines are used (ACMG or Mayo clinic respectively). We have catalogued a spectrum of Irish autosomal dominant PKD pathogenic variants including 36 novel variants. We illustrate how apparently unrelated individuals carrying the same autosomal dominant pathogenic variant are highly likely to have inherited that variant from a common ancestor. We highlight issues surrounding the implementation of the ACMG guidelines for variant pathogenicity interpretation in PKD, which have important implications for clinical genetics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-020-00806-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110806PMC
May 2021

Barriers and Considerations for Diagnosing Rare Diseases in Indigenous Populations.

Front Pediatr 2020 14;8:579924. Epub 2020 Dec 14.

Western Australian Register of Developmental Anomalies, Perth, WA, Australia.

Advances in omics and specifically genomic technologies are increasingly transforming rare disease diagnosis. However, the benefits of these advances are disproportionately experienced within and between populations, with Indigenous populations frequently experiencing diagnostic and therapeutic inequities. The International Rare Disease Research Consortium (IRDiRC) multi-stakeholder partnership has been advancing toward the vision of all people living with a rare disease receiving an accurate diagnosis, care, and available therapy within 1 year of coming to medical attention. In order to further progress toward this vision, IRDiRC has created a taskforce to explore the access barriers to diagnosis of rare genetic diseases faced by Indigenous peoples, with a view of developing recommendations to overcome them. Herein, we provide an overview of the state of play of current barriers and considerations identified by the taskforce, to further stimulate awareness of these issues and the passage toward solutions. We focus on analyzing barriers to accessing genetic services, participating in genomic research, and other aspects such as concerns about data sharing, the handling of biospecimens, and the importance of capacity building.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2020.579924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767925PMC
December 2020

Rare Disease Research Partnership (RAinDRoP): a collaborative approach to identify research priorities for rare diseases in Ireland.

HRB Open Res 2020 11;3:13. Epub 2020 Nov 11.

UCD School of Nursing, Midwifery and Health Systems, University College Dublin, Belfield, County Dublin, D04 V1W8, Ireland.

Rare diseases are individually rare, but collectively these conditions are common. Research on rare diseases are currently focused on disease-specific needs rather than a life-course perspective. The Rare Disease Research Partnership (RAinDRoP) was established in 2018 to bring together a wide variety of diverse voices in the rare disease community in Ireland and form a research partnership. A participatory multiple phase approach was used to identify research priorities for rare diseases. The research process involved three main phases: Phase I, Public Consultation Survey(PCS); Phase II, Research Prioritisation Workshop (RPW); Phase III, Public Prioritisation Ranking Survey (PRS). The time frame for the entire study was from November 2018 to June 2019. In total, 240 individuals completed the phase I, of which only 96 survey participants provided information on their background,  32% (n=31) self-identified as a person living with a rare disease(s). One thousand and fifteen statements were collected, which reflected issues and shared challenges in rare diseases. MSExcel was used to gain frequencies and percentages. Phase II was focused on three main themes (1) Route to Diagnosis (2) Living with Rare Disease (3) Integrated and Palliative Care. 42 participants engaged at each workshop. Seventy-five individuals completed the phase III prioritisation ranking survey and ranked the top 15 research priorities.  The top five priorities were (1)Support at the time of diagnosis, (2) Diagnostic test for rare diseases (3)Education and training (4) Patient voice (5) Data sharing and integration of services for rare diseases. The research priorities identified here for rare diseases were developed jointly in collaboration with patients, families, healthcare professionals and policymakers. So, we encourage researchers, funding bodies and other stakeholders to use this priority list as a guiding document for future research work to improve the health and lives of people living with rare diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12688/hrbopenres.13017.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702160PMC
November 2020

BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms.

Am J Hum Genet 2020 12 23;107(6):1096-1112. Epub 2020 Nov 23.

Division of Clinical Genetics, Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA.

SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features. Notably, the majority of individuals lack the fifth digit/nail hypoplasia phenotype, a hallmark of most SSRIDDs. To confirm the role of BICRA in the development of these phenotypes, we performed functional characterization of the zebrafish and Drosophila orthologs of BICRA. In zebrafish, a mutation of bicra that mimics one of the loss-of-function variants leads to craniofacial defects possibly akin to the dysmorphic facial features seen in individuals harboring putatively pathogenic BICRA variants. We further show that Bicra physically binds to other non-canonical ncBAF complex members, including the BRD9/7 ortholog, CG7154, and is the defining member of the ncBAF complex in flies. Like other SWI/SNF complex members, loss of Bicra function in flies acts as a dominant enhancer of position effect variegation but in a more context-specific manner. We conclude that haploinsufficiency of BICRA leads to a unique SSRIDD in humans whose phenotypes overlap with those previously reported.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820627PMC
December 2020

A retrospective review of the contribution of rare diseases to paediatric mortality in Ireland.

Orphanet J Rare Dis 2020 11 4;15(1):311. Epub 2020 Nov 4.

Children's Health Ireland, Temple Street, Dublin, Republic of Ireland.

Aims: To ascertain the number of paediatric deaths (0-14 years) with an underlying rare disease in the Republic of Ireland between the years 2006-2016, and to analyse bed usage by a paediatric cohort of rare disease inpatients prior to in-hospital death.

Background: Rare diseases are often chronically debilitating and sometimes life-threatening diseases, with the majority (69.9%) of rare diseases being of paediatric onset. The Orphanet database contains information on 6172 unique rare diseases. Under-representation of rare diseases in hospital healthcare coding systems leads to a paucity of rare disease epidemiological data required for healthcare planning. Studies have cited variable incidence rates for rare disease, however the burden of rare diseases to healthcare services still remains unclear. This study represents a thorough effort to identify the percentage of child mortality and paediatric bed usage attributable to rare diseases in the Republic of Ireland, thus addressing a major gap in the rare disease field.

Methods: Retrospective analysis of paediatric death registration details for the Republic of Ireland in the 11-year period 2006-2016 from the National Paediatric Mortality Register. Data was subcategorised as Neonatal (0-28 days), Post Neonatal (29 days < 1 year) and older (1-14 years). Bed usage data (ICD-10 code, narrative and usage) of paediatric inpatients who died during hospitalisation from January 2015 to December 2016 was extracted from the National Quality Assurance Improvement System of in-patient data. Orphacodes were assigned to rare disease cases from ICD-10 codes or diagnostic narrative of both datasets.

Results: There were 4044 deaths registered from 2006-2016, aged < 15 years, of these 2368 (58.6%) had an underlying rare disease. Stratifying by age group; 55.6% (1140/2050) of neonatal deaths had a rare disease, 57.8% (450/778) post-neonatal, and 64% (778/1216) of children aged 1-14 years. Mortality coding using ICD-10 codes identified 42% of rare disease cases with the remainder identified using death certificate narrative records. Rare disease patients occupied 87% of bed days used by children < 15 years who died during hospitalisation from January 2015 to December 2016.

Conclusion: Additional routine rare disease coding is necessary to identify rare diseases within Irish healthcare systems to enable better healthcare planning. Rare disease patients are overrepresented in paediatric mortality statistics and in-patient length of stay during hospital admission prior to death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-020-01574-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641805PMC
November 2020

Dying to see you? Deaths on a clinical genetics waiting list in the Republic of Ireland; what are the consequences?

J Community Genet 2021 Jan 29;12(1):121-127. Epub 2020 Oct 29.

Department of Clinical Genetics, Children's Hospital Ireland at Crumlin, Dublin, 12, Ireland.

Attempts to put a value on a clinical genetic consultation are challenging as outcome measures are not easily quantified. One technique is to consider the negative consequences to a referred patient who is never seen. In order to estimate possible negative effects and by default the value of a genetics consultation; we sought to identify the consequences both to the proband, who died awaiting appointment, and their relatives. We audited 45 referrals to our service who died on our waiting list since 2008. Of these, 39/45 were new referrals, and the remainder, 6/45, died awaiting a follow up appointment. Relatives from 14/45 (31%) families have been counselled since the proband's death. We estimated a minimal total of 207 living first degree relatives to 45 probands. The majority (30/45) were referred for cancer risk estimation (1 predictive, 29 diagnostic), 11 developmental delay/dysmorphology referrals, 3 cardiac genetic referrals, (2 predictive testing, 1 segregation analysis) and 1 a referral for early onset dementia. The deaths of 17/45 cases were judged by us as having potentially significantly impacted the health of 76 first-degree relatives; 13/45 have potentially moderately impacted the health of 57 first-degree relatives; 12/45 posed a minimal impact to their relatives; and in 3/45 cases families were fully counselled. For each proband, significantly or moderately negatively impacted (n = 30), they have a minimum of 4.4 first-degree relatives, range 1-11, total = 133.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12687-020-00491-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846633PMC
January 2021

Integration of genetic and histopathology data in interpretation of kidney disease.

Nephrol Dial Transplant 2020 07;35(7):1113-1132

Department of Nephrology and Transplantation, Beaumont Hospital, Dublin, Ireland.

For many years renal biopsy has been the gold standard for diagnosis in many forms of kidney disease. It provides rapid, accurate and clinically useful information in most individuals with kidney disease. However, in recent years, other diagnostic modalities have become available that may provide more detailed and specific diagnostic information in addition to, or instead of, renal biopsy. Genomics is one of these modalities. Previously prohibitively expensive and time consuming, it is now increasingly available and practical in a clinical setting for the diagnosis of inherited kidney disease. Inherited kidney disease is a significant cause of kidney disease, in both the adult and paediatric populations. While individual inherited kidney diseases are rare, together they represent a significant burden of disease. Because of the heterogenicity of inherited kidney disease, diagnosis and management can be a challenge and often multiple diagnostic modalities are needed to arrive at a diagnosis. We present updates in genomic medicine for renal disease, how genetic testing integrates with our knowledge of renal histopathology and how the two modalities may interact to enhance patient care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfaa176DOI Listing
July 2020

National Newborn Screening for cystic fibrosis in the Republic of Ireland: genetic data from the first 6.5 years.

Eur J Hum Genet 2020 12 1;28(12):1669-1674. Epub 2020 Jun 1.

Department of Clinical Genetics, Children's Health Ireland (CHI) at Crumlin, Dublin, Ireland.

Cystic fibrosis (CF) is the most common life-limiting autosomal recessive disease in the Republic of Ireland (ROI), with a previously quoted incidence of 1 in 1353 and carrier rate of 1 in 19. The National Newborn Screening (NBS) for CF was incorporated in July 2011 in the ROI. A cut-off point of the top 1% Immunoreactive Trypsinogen (IRT) was taken as an indication for 38 CFTR variant panel to maximise identification of affected CF cases and to minimise detection of carriers. All neonates from July 2011 to Dec 2017 with an elevated IRT on NBS were tested with 38 CFTR mutation panel and included. Clinical and laboratory database were analysed. In the first 6.5 years a total of 5,053 newborns (1.16% of total births) were screened with 38 CFTR panel. 170 CF affected cases, 320 unaffected carriers, 32 CF Screening Positive Inconclusive Diagnosis (CFSPID) were identified. There was one missed diagnosis. The most common disease-causing variant was c.1521_1523delCTT (p.(Phe508del)) followed by c.1652G>A (p.(Gly551Asp)). 95 out of 170 (55%) affected newborns were homozygous for c.1521_1523delCTT (p.(Phe08del)) and 25 (15%) carried at least one copy of c.1652G>A (p.(Gly551Asp)). Hence, 70% of affected newborns were eligible for CFTR modulator treatment. The NBS programme has identified almost triple the number of affected newborn with c.1652G>A (p.(Gly551Asp)) than previously quoted figures and identified less than 50% of carriers than predicted. The revised incidence and carrier frequency of CF in the ROI is 1 in 2570 and 1 in 25, respectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-020-0661-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784902PMC
December 2020

Phenotypic Variability in Leukoencephalopathy with Brain Calcifications and Cysts: Case Report of Siblings from an Irish Traveller Family with a Homozygous SNORD118 Mutation.

J Mol Neurosci 2020 Sep 2;70(9):1354-1356. Epub 2020 May 2.

Department of Neurology, Mater Misericordiae University Hospital, Dublin, Ireland.

Leukoencephalopathy with brain calcifications and cysts (LCC) is a rare cerebral microangiopathy, the cause of which was recently determined to be recessively inherited mutations in the SNORD118 gene. We report the case of a 32-year-old Irish Traveller woman who presented to the emergency department in convulsive status epilepticus with abnormal neuroimaging features characteristic of LCC. Her medical history consisted of epilepsy, intellectual impairment, previous craniotomies for excision of cerebral cysts and resection of a tibial osteogenic sarcoma. Whole exome sequencing identified a previously described homozygous variant, NR_033294.1 n.*5C>G, in the 3' UTR of the SNORD118 gene. Her sister was subsequently found to be homozygous for the same variant but with a significantly milder clinical phenotype consisting of migraine without aura and mild, non-specific, cerebral white matter changes on neuroimaging. Knowledge of the existence of LCC within this population means that targeted genetic testing for this specific mutation should be considered in Irish Traveller patients presenting with the characteristic clinical and radiological features. Given the striking phenotypic variability seen within this family, LCC should also be considered in Irish Traveller patients even in the absence of the complete radiological triad.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12031-020-01550-7DOI Listing
September 2020

DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes.

Am J Hum Genet 2020 05 2;106(5):596-610. Epub 2020 Apr 2.

Department of Oncology and Hemato-oncology, University of Milan, Milan 20122, Italy; Laboratory of Stem Cell Epigenetics, IEO, European Institute of Oncology, IRCCS, Milan 20139, Italy; Human Technopole, Center for Neurogenomics, Via Cristina Belgioioso 171, Milan 20157, Italy.

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2020.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212265PMC
May 2020

A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome.

Genet Med 2020 05 17;22(5):867-877. Epub 2020 Jan 17.

Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, UK.

Purpose: To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1).

Methods: Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism.

Results: The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective software-based facial analysis metrics, and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to ɑ-helical transition.

Conclusion: KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0743-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200597PMC
May 2020

X-linked infantile spinal muscular atrophy (SMAX2) caused by novel c.1681G>A substitution in the UBA1 gene, expanding the phenotype.

Neuromuscul Disord 2020 01 14;30(1):35-37. Epub 2019 Nov 14.

Department of Paediatric Neurology and Neurophysiology, Children's University Hospital, Temple Street, Dublin, Ireland.

X-linked infantile spinal muscular atrophy (SMAX2), OMIM 301830, is a rare, severe form of spinal muscular atrophy, caused by variants in the Ubiquitin like modifier-activating enzyme 1 (UBA1) gene. Clinical features reported to date include marked hypotonia, areflexia, arthrogryposis, contractures, myopathic facies and tongue fibrillations. Previous reports have included a history of contractures. We report a male patient presenting following a normal pregnancy with typical symptoms of X-linked infantile spinal muscular atrophy including hypotonia, weakness, areflexia and respiratory insufficiency, however contractures were absent. There was a significant family history of neuromuscular disease on the maternal side, with several male relatives all dying before the age of six months. Creatine Kinase was mildly elevated, MRI Brain was normal and neurophysiological testing revealed a diffuse motor neuronopathy. Genetic testing for SMN1 gene was normal. UBA1 sequencing revealed a maternally inherited hemizygous familial variant [c.1681G>A p. (Asp561Asn)], which has not been previously reported.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nmd.2019.11.004DOI Listing
January 2020

The phenotype of Sotos syndrome in adulthood: A review of 44 individuals.

Am J Med Genet C Semin Med Genet 2019 12 3;181(4):502-508. Epub 2019 Sep 3.

Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.

Sotos syndrome is an overgrowth-intellectual disability (OGID) syndrome caused by NSD1 pathogenic variants and characterized by a distinctive facial appearance, an intellectual disability, tall stature and/or macrocephaly. Other associated clinical features include scoliosis, seizures, renal anomalies, and cardiac anomalies. However, many of the published Sotos syndrome clinical descriptions are based on studies of children; the phenotype in adults with Sotos syndrome is not yet well described. Given that it is now 17 years since disruption of NSD1 was shown to cause Sotos syndrome, many of the children first reported are now adults. It is therefore timely to investigate the phenotype of 44 adults with Sotos syndrome and NSD1 pathogenic variants. We have shown that adults with Sotos syndrome display a wide spectrum of intellectual ability with functioning ranging from fully independent to fully dependent. Reproductive rates are low. In our cohort, median height in adult women is +1.9 SD and men +0.5 SD. There is a distinctive facial appearance in adults with a tall, square, prominent chin. Reassuringly, adults with Sotos syndrome are generally healthy with few new medical issues; however, lymphedema, poor dentition, hearing loss, contractures and tremor have developed in a small number of individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.c.31738DOI Listing
December 2019

A clinical scoring system for congenital contractural arachnodactyly.

Genet Med 2020 01 18;22(1):124-131. Epub 2019 Jul 18.

Center for Human Genetics, Institute of Pathology and Genetics (IPG), Gosselies, Belgium.

Purpose: Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and kyphoscoliosis as main features. Due to its rarity, rather aspecific clinical presentation, and overlap with other conditions including Marfan syndrome, the diagnosis is challenging, but important for prognosis and clinical management. CCA is caused by pathogenic variants in FBN2, encoding fibrillin-2, but locus heterogeneity has been suggested. We designed a clinical scoring system and diagnostic criteria to support the diagnostic process and guide molecular genetic testing.

Methods: In this retrospective study, we assessed 167 probands referred for FBN2 analysis and classified them into a FBN2-positive (n = 44) and FBN2-negative group (n = 123) following molecular analysis. We developed a 20-point weighted clinical scoring system based on the prevalence of ten main clinical characteristics of CCA in both groups.

Results: The total score was significantly different between the groups (P < 0.001) and was indicative for classifying patients into unlikely CCA (total score <7) and likely CCA (total score ≥7) groups.

Conclusions: Our clinical score is helpful for clinical guidance for patients suspected to have CCA, and provides a quantitative tool for phenotyping in research settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0609-8DOI Listing
January 2020

A novel NAA10 p.(R83H) variant with impaired acetyltransferase activity identified in two boys with ID and microcephaly.

BMC Med Genet 2019 06 7;20(1):101. Epub 2019 Jun 7.

Department of Biomedicine, University of Bergen, Jonas Lies vei 91, NO-5020, Bergen, Norway.

Background: N-terminal acetylation is a common protein modification in human cells and is catalysed by N-terminal acetyltransferases (NATs), mostly cotranslationally. The NAA10-NAA15 (NatA) protein complex is the major NAT, responsible for acetylating ~ 40% of human proteins. Recently, NAA10 germline variants were found in patients with the X-linked lethal Ogden syndrome, and in other familial or de novo cases with variable degrees of developmental delay, intellectual disability (ID) and cardiac anomalies.

Methods: Here we report a novel NAA10 (NM_003491.3) c.248G > A, p.(R83H) missense variant in NAA10 which was detected by whole exome sequencing in two unrelated boys with intellectual disability, developmental delay, ADHD like behaviour, very limited speech and cardiac abnormalities. We employ in vitro acetylation assays to functionally test the impact of this variant on NAA10 enzyme activity.

Results: Functional characterization of NAA10-R83H by in vitro acetylation assays revealed a reduced enzymatic activity of monomeric NAA10-R83H. This variant is modelled to have an altered charge density in the acetyl-coenzyme A (Ac-CoA) binding region of NAA10.

Conclusions: We show that NAA10-R83H has a reduced monomeric catalytic activity, likely due to impaired enzyme-Ac-CoA binding. Our data support a model where reduced NAA10 and/or NatA activity cause the phenotypes observed in the two patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12881-019-0803-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554967PMC
June 2019

The clinical presentation caused by truncating CHD8 variants.

Clin Genet 2019 07 14;96(1):72-84. Epub 2019 May 14.

Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.

Variants in the chromodomain helicase DNA-binding protein 8 (CHD8) have been associated with intellectual disability (ID), autism spectrum disorders (ASDs) and overgrowth and CHD8 is one of the causative genes for OGID (overgrowth and ID). We investigated 25 individuals with CHD8 protein truncating variants (PTVs), including 10 previously unreported patients and found a male to female ratio of 2.7:1 (19:7) and a pattern of common features: macrocephaly (62.5%), tall stature (47%), developmental delay and/or intellectual disability (81%), ASDs (84%), sleep difficulties (50%), gastrointestinal problems (40%), and distinct facial features. Most of the individuals in this cohort had moderate-to-severe ID, some had regression of speech (37%), seizures (27%) and hypotonia (27%) and two individuals were non-ambulant. Our study shows that haploinsufficiency of CHD8 is associated with a distinctive OGID syndrome with pronounced autistic traits and supports a sex-dependent penetrance of CHD8 PTVs in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13554DOI Listing
July 2019

Managing uncertainty in inherited cardiac pathologies-an international multidisciplinary survey.

Eur J Hum Genet 2019 08 12;27(8):1178-1185. Epub 2019 Apr 12.

Our Lady's Children's Hospital Crumlin, Dublin 12, Dublin, Ireland.

Multi-gene testing is useful in genetically heterogeneous conditions, including inherited cardiac pathologies. Increasing the number of genes analysed increases diagnostic yield of variants of certain, likely, or uncertain pathogenicity. Concerns exist regarding management of variants of uncertain/likely pathogenicity in conditions of oligogenic inheritance or variable expressivity. We surveyed a sample of colleagues across different specialties and departments internationally to compare management of patients with class 3 or class 4 variants in genes associated with non-syndromic cardiomyopathy or arrhythmia. An electronic survey regarding clinical management of variants ( www.surveymonkey.com/r/cardiacvariants ) was designed and distributed to colleagues internationally via professional bodies and direct email. 150 respondents (88 centres, 27 countries) completed the survey, most of whom were Clinical Geneticists or Genetic Counsellors. Most respondents offer pre-symptomatic testing to asymptomatic relatives of an individual with class 4 or class 5 variants. A minority of respondents offer pre-symptomatic testing for class 3 variants. Considering class 4 variants, 22 (15%) are fully reassuring that the patient with a negative predictive test would not develop the familial phenotype, while 123 (82%) counselled patients about the possibility of variant reclassification. Variability existed between and within centres and specialties. Multiple "free text" comments were provided. Recurring themes including need for multidisciplinary input, technical concerns, and concern regarding duty to review variants of uncertain significance. This study demonstrates that variability in management of likely pathogenic/uncertain variants exists. Close multi-disciplinary input is essential. The development of disorder or gene-specific evidence-based guidelines might ameliorate uncertainty in management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-019-0391-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777443PMC
August 2019

Towards establishing consistency in triage in a tertiary specialty.

Eur J Hum Genet 2019 04 8;27(4):547-555. Epub 2019 Jan 8.

Department of Clinical Genetics, Our Lady's Children's Hospital Crumlin, Dublin, Ireland.

Clinical Genetics services provide a diagnostic, counselling and genetic testing service for children and adults affected by, or at risk of, a genetic condition, most of which are rare, and/or genetically heterogeneous. Appropriate triage of referrals is crucial to ensure that the most urgent referrals are seen as quickly as possible, without negatively impacting the waiting times of less urgent cases. We aimed to examine triage practice in six Clinical Genetic centres across the United Kingdom and Ireland. Thirteen simulated referrals were drafted based on common referrals to Clinical Genetics. Copies of each referral were forwarded to each centre, where 10 nominated clinicians were asked to triage each referral. Triaged referrals were returned to the coordinating author for analysis. An electronic questionnaire was contemporaneously completed by clinical leads in each unit to gather local demographic details and local operating procedures relevant to triage. Widespread inconsistencies were noted both within and between units, with respect to the acceptance of referrals to the services, prioritisation and designated clinic type. Referral rates, staffing levels and waiting lists varied widely between units. Inconsistencies observed between units are likely influenced by a number of factors, including staffing levels, referral rates and average family size. Inconsistency within units likely reflects the complex nature of many Clinical Genetic referrals, and triage guidelines should help improve decision-making in this setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-018-0322-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460635PMC
April 2019

Pathogenicity and selective constraint on variation near splice sites.

Genome Res 2019 02 26;29(2):159-170. Epub 2018 Dec 26.

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.

Mutations that perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7833 probands with developmental disorders (DDs) and their unaffected parents, as well as more than 60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice sites and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects, and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. By using mutational burden analyses in this large cohort of proband-parent trios, we could estimate in an unbiased manner the relative contributions of mutations at canonical dinucleotides (73%) and flanking noncanonical positions (27%), and calculate the positive predictive value of pathogenicity for different classes of mutations. We identified 18 patients with likely diagnostic de novo mutations in dominant DD-associated genes at noncanonical positions in splice sites. We estimate 35%-40% of pathogenic variants in noncanonical splice site positions are missing from public databases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/gr.238444.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360807PMC
February 2019

Quantifying the contribution of recessive coding variation to developmental disorders.

Science 2018 12 8;362(6419):1161-1164. Epub 2018 Nov 8.

Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.

We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, and , and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aar6731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726470PMC
December 2018

Heterozygous loss-of-function variants of MEIS2 cause a triad of palatal defects, congenital heart defects, and intellectual disability.

Eur J Hum Genet 2019 02 5;27(2):278-290. Epub 2018 Oct 5.

Department of Otorhinolaryngology-Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium.

Deletions on chromosome 15q14 are a known chromosomal cause of cleft palate, typically co-occurring with intellectual disability, facial dysmorphism, and congenital heart defects. The identification of patients with loss-of-function variants in MEIS2, a gene within this deletion, suggests that these features are attributed to haploinsufficiency of MEIS2. To further delineate the phenotypic spectrum of the MEIS2-related syndrome, we collected 23 previously unreported patients with either a de novo sequence variant in MEIS2 (9 patients), or a 15q14 microdeletion affecting MEIS2 (14 patients). All but one de novo MEIS2 variant were identified by whole-exome sequencing. One variant was found by targeted sequencing of MEIS2 in a girl with a clinical suspicion of this syndrome. In addition to the triad of palatal defects, heart defects, and developmental delay, heterozygous loss of MEIS2 results in recurrent facial features, including thin and arched eyebrows, short alae nasi, and thin vermillion. Genotype-phenotype comparison between patients with 15q14 deletions and patients with sequence variants or intragenic deletions within MEIS2, showed a higher prevalence of moderate-to-severe intellectual disability in the former group, advocating for an independent locus for psychomotor development neighboring MEIS2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-018-0281-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336847PMC
February 2019

Refining the phenotype associated with GNB1 mutations: Clinical data on 18 newly identified patients and review of the literature.

Am J Med Genet A 2018 11 8;176(11):2259-2275. Epub 2018 Sep 8.

Carle Physician Group, Urbana, Illinois.

De novo germline mutations in GNB1 have been associated with a neurodevelopmental phenotype. To date, 28 patients with variants classified as pathogenic have been reported. We add 18 patients with de novo mutations to this cohort, including a patient with mosaicism for a GNB1 mutation who presented with a milder phenotype. Consistent with previous reports, developmental delay in these patients was moderate to severe, and more than half of the patients were non-ambulatory and nonverbal. The most observed substitution affects the p.Ile80 residue encoded in exon 6, with 28% of patients carrying a variant at this residue. Dystonia and growth delay were observed more frequently in patients carrying variants in this residue, suggesting a potential genotype-phenotype correlation. In the new cohort of 18 patients, 50% of males had genitourinary anomalies and 61% of patients had gastrointestinal anomalies, suggesting a possible association of these findings with variants in GNB1. In addition, cutaneous mastocytosis, reported once before in a patient with a GNB1 variant, was observed in three additional patients, providing further evidence for an association to GNB1. We will review clinical and molecular data of these new cases and all previously reported cases to further define the phenotype and establish possible genotype-phenotype correlations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.40472DOI Listing
November 2018

De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder.

Am J Hum Genet 2018 08 26;103(2):305-316. Epub 2018 Jul 26.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.

Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2018.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080769PMC
August 2018
-->