-
Genome Medicine Mar 2021We report the findings from 4437 individuals (3219 patients and 1218 relatives) who have been analyzed by whole genome sequencing (WGS) at the Genomic Medicine Center...
BACKGROUND
We report the findings from 4437 individuals (3219 patients and 1218 relatives) who have been analyzed by whole genome sequencing (WGS) at the Genomic Medicine Center Karolinska-Rare Diseases (GMCK-RD) since mid-2015. GMCK-RD represents a long-term collaborative initiative between Karolinska University Hospital and Science for Life Laboratory to establish advanced, genomics-based diagnostics in the Stockholm healthcare setting.
METHODS
Our analysis covers detection and interpretation of SNVs, INDELs, uniparental disomy, CNVs, balanced structural variants, and short tandem repeat expansions. Visualization of results for clinical interpretation is carried out in Scout-a custom-developed decision support system. Results from both singleton (84%) and trio/family (16%) analyses are reported. Variant interpretation is done by 15 expert teams at the hospital involving staff from three clinics. For patients with complex phenotypes, data is shared between the teams.
RESULTS
Overall, 40% of the patients received a molecular diagnosis ranging from 19 to 54% for specific disease groups. There was heterogeneity regarding causative genes (n = 754) with some of the most common ones being COL2A1 (n = 12; skeletal dysplasia), SCN1A (n = 8; epilepsy), and TNFRSF13B (n = 4; inborn errors of immunity). Some causative variants were recurrent, including previously known founder mutations, some novel mutations, and recurrent de novo mutations. Overall, GMCK-RD has resulted in a large number of patients receiving specific molecular diagnoses. Furthermore, negative cases have been included in research studies that have resulted in the discovery of 17 published, novel disease-causing genes. To facilitate the discovery of new disease genes, GMCK-RD has joined international data sharing initiatives, including ClinVar, UDNI, Beacon, and MatchMaker Exchange.
CONCLUSIONS
Clinical WGS at GMCK-RD has provided molecular diagnoses to over 1200 individuals with a broad range of rare diseases. Consolidation and spread of this clinical-academic partnership will enable large-scale national collaboration.
Topics: Cohort Studies; DNA Copy Number Variations; Delivery of Health Care; Genetic Heterogeneity; Genomics; High-Throughput Nucleotide Sequencing; Humans; Information Dissemination; Inheritance Patterns; Microsatellite Repeats; Mutation; Rare Diseases; Sweden; Uniparental Disomy; Whole Genome Sequencing
PubMed: 33726816
DOI: 10.1186/s13073-021-00855-5 -
Human Molecular Genetics Apr 2010Mosaic aneuploidy and uniparental disomy (UPD) arise from mitotic or meiotic events. There are differences between these mechanisms in terms of (i) impact on embryonic...
Mosaic aneuploidy and uniparental disomy (UPD) arise from mitotic or meiotic events. There are differences between these mechanisms in terms of (i) impact on embryonic development; (ii) co-occurrence of mosaic trisomy and UPD and (iii) potential recurrence risks. We used a genome-wide single nucleotide polymorphism (SNP) array to study patients with chromosome aneuploidy mosaicism, UPD and one individual with XX/XY chimerism to gain insight into the developmental mechanism and timing of these events. Sixteen cases of mosaic aneuploidy originated mitotically, and these included four rare trisomies and all of the monosomies, consistent with the influence of selective factors. Five trisomies arose meiotically, and three of the five had UPD in the disomic cells, confirming increased risk for UPD in the case of meiotic non-disjunction. Evidence for the meiotic origin of aneuploidy and UPD was seen in the patterns of recombination visible during analysis with 1-3 crossovers per chromosome. The mechanisms of formation of the UPD included trisomy rescue, with and without concomitant trisomy, monosomy rescue, and mitotic formation of a mosaic segmental UPD. UPD was also identified in an XX/XY chimeric individual, with one cell line having complete maternal UPD consistent with a parthenogenetic origin. Utilization of SNP arrays allows simultaneous evaluation of genomic alterations and insights into aneuploidy and UPD mechanisms. Differentiation of mitotic and meiotic origins for aneuploidy and UPD supports existence of selective factors against full trisomy of some chromosomes in the early embryo and provides data for estimation of recurrence and disease mechanisms.
Topics: Aneuploidy; Chimerism; Humans; Meiosis; Monosomy; Mosaicism; Polymorphism, Single Nucleotide; Sex Chromosomes; Trisomy; Uniparental Disomy
PubMed: 20053666
DOI: 10.1093/hmg/ddq003 -
Temple syndrome and Kagami-Ogata syndrome: clinical presentations, genotypes, models and mechanisms.Human Molecular Genetics Sep 2020Temple syndrome (TS) and Kagami-Ogata syndrome (KOS) are imprinting disorders caused by absence or overexpression of genes within a single imprinted cluster on human... (Review)
Review
Temple syndrome (TS) and Kagami-Ogata syndrome (KOS) are imprinting disorders caused by absence or overexpression of genes within a single imprinted cluster on human chromosome 14q32. TS most frequently arises from maternal UPD14 or epimutations/deletions on the paternal chromosome, whereas KOS most frequently arises from paternal UPD14 or epimutations/deletions on the maternal chromosome. In this review, we describe the clinical symptoms and genetic/epigenetic features of this imprinted region. The locus encompasses paternally expressed protein-coding genes (DLK1, RTL1 and DIO3) and maternally expressed lncRNAs (MEG3/GTL2, RTL1as and MEG8), as well as numerous miRNAs and snoRNAs. Control of expression is complex, with three differentially methylated regions regulating germline, placental and tissue-specific transcription. The strong conserved synteny between mouse chromosome 12aF1 and human chromosome 14q32 has enabled the use of mouse models to elucidate imprinting mechanisms and decipher the contribution of genes to the symptoms of TS and KOS. In this review, we describe relevant mouse models and highlight their value to better inform treatment options for long-term management of TS and KOS patients.
Topics: Abnormalities, Multiple; Animals; Chromosome Disorders; Chromosomes, Human, Pair 14; Disease Models, Animal; Genomic Imprinting; Hallux; Humans; Intellectual Disability; Mice; Nails, Malformed; Phenotype; Thumb; Uniparental Disomy
PubMed: 32592473
DOI: 10.1093/hmg/ddaa133 -
Genetics in Medicine : Official Journal... Feb 2022Genomic testing, including single-nucleotide variation (formerly single-nucleotide polymorphism)-based chromosomal microarray and exome and genome sequencing, can detect...
Interpretation and reporting of large regions of homozygosity and suspected consanguinity/uniparental disomy, 2021 revision: A technical standard of the American College of Medical Genetics and Genomics (ACMG).
Genomic testing, including single-nucleotide variation (formerly single-nucleotide polymorphism)-based chromosomal microarray and exome and genome sequencing, can detect long regions of homozygosity (ROH) within the genome. Genomic testing can also detect possible uniparental disomy (UPD). Platforms that can detect ROH and possible UPD have matured since the initial American College of Medical Genetics and Genomics (ACMG) standard was published in 2013, and the detection of ROH and UPD by these platforms has shown utility in diagnosis of patients with genetic/genomic disorders. The presence of these segments, when distributed across multiple chromosomes, may indicate a familial relationship between the proband's parents. This technical standard describes the detection of possible consanguinity and UPD by genomic testing, as well as the factors confounding the inference of a specific parental relationship or UPD. Current bioethical and legal issues regarding detection and reporting of consanguinity are also discussed.
Topics: Consanguinity; Genetics, Medical; Genomics; Homozygote; Humans; Polymorphism, Single Nucleotide; Uniparental Disomy; United States
PubMed: 34906464
DOI: 10.1016/j.gim.2021.10.004 -
Genetics in Medicine : Official Journal... Jul 2020
Topics: Diagnostic Techniques and Procedures; Genetic Testing; Genetics, Medical; Genomic Imprinting; Genomics; Humans; Uniparental Disomy; United States
PubMed: 32296163
DOI: 10.1038/s41436-020-0782-9 -
Taiwanese Journal of Obstetrics &... Mar 2022Uniparental disomy (UPD) is the inheritance of both homologous chromosomes from a single parent. Most chromosomes involving UPD have no pathogenic effects. However,... (Review)
Review
Uniparental disomy (UPD) is the inheritance of both homologous chromosomes from a single parent. Most chromosomes involving UPD have no pathogenic effects. However, abnormal phenotypes in cases with UPD can be mainly caused by disrupting genetic imprinting and by uncovering harmful autosomal recessive mutations. The documented phenotypes of UPD associated with imprinted genes include maternal UPD for chromosomes 7, 11, 14, 15, 16, and 20, and paternal UPD for chromosomes 6, 11, 14, 15, and 20. Prenatal awareness of UPD is important to provide accurate genetic counseling and prenatal UPD test is suggested when abnormal fetal ultrasound with suspicious phenotypes for UPD syndromes caused by genetic imprinting disorders or presence of chromosomal aberrations involving the imprinted chromosomes.
Topics: Chromosome Aberrations; Female; Genetic Counseling; Genomic Imprinting; Humans; Pregnancy; Prenatal Diagnosis; Uniparental Disomy
PubMed: 35361378
DOI: 10.1016/j.tjog.2022.02.006 -
American Journal of Medical Genetics.... Aug 2021Trisomy 9 mosaic syndrome (T9M) is a rare condition characterized by multiorgan system involvement including craniofacial dysmorphisms, cardiac, genitourinary (GU),... (Review)
Review
Trisomy 9 mosaic syndrome (T9M) is a rare condition characterized by multiorgan system involvement including craniofacial dysmorphisms, cardiac, genitourinary (GU), skeletal, and central nervous system (CNS) abnormalities. Although more than 100 cases have been reported in the literature, a comprehensive review has not been performed nor have clinical guidelines been established. Therefore, we describe the clinical features of 16 additional patients, review features of previously reported individuals, and suggest clinical guidelines. Our findings expand the clinical phenotype of T9M, including novel features of amblyopia, astigmatism, corectopia of pupil, posterior embryotoxon, and diaphragmatic eventration. Most patients had prenatal and perinatal issues, particularly from respiratory, growth, and feeding standpoints. Although small birth parameters were common, long-term growth trends varied widely. An association with advanced parental ages was also identified. The spectrum of growth and development was wide, ranging from nonverbal patients to those able to participate in educational programs with age-appropriate peers. The severity of clinical outcomes was unrelated to blood lymphocyte mosaicism levels. Microarray analysis had a higher diagnostic rate compared to standard karyotype analysis and should be utilized if this diagnosis is suspected. Future longitudinal studies will be key to monitor long-term outcomes of individuals with T9M and determine best practices for clinical management.
Topics: Adolescent; Adult; Brain; Child; Child, Preschool; Chromosomes, Human, Pair 9; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; Growth Charts; Humans; Infant; Infant, Newborn; Male; Mosaicism; Phenotype; Trisomy; Uniparental Disomy; Young Adult
PubMed: 33969943
DOI: 10.1002/ajmg.a.62251 -
Ugeskrift For Laeger Jun 2021We report a boy with congenital hemihyperplasia, umbilical hernia and temporary neonatal hypoglycemia, who was confirmed to have BWS caused by paternal uniparental...
We report a boy with congenital hemihyperplasia, umbilical hernia and temporary neonatal hypoglycemia, who was confirmed to have BWS caused by paternal uniparental disomy of chromosome 11p15.5. Additional phenotypic features comprising scoliosis, nephromegaly, focal partial epilepsy and delayed psychomotor development were coherent with the underlying genotype. This case emphasizes the importance of identifying the underlying genetic variant in order to acknowledge and manage the associated clinical complications and specific risk profile.
Topics: Beckwith-Wiedemann Syndrome; Hernia, Umbilical; Humans; Hyperplasia; Infant, Newborn; Kidney Diseases; Male; Uniparental Disomy
PubMed: 34120690
DOI: No ID Found -
Translational Pediatrics Apr 2014Robertsonian translocations (ROBs) are whole arm rearrangements involving the acrocentric chromosomes 13-15 and 21-22 and carriers are at increased risk for aneuploidy... (Review)
Review
Robertsonian translocations (ROBs) are whole arm rearrangements involving the acrocentric chromosomes 13-15 and 21-22 and carriers are at increased risk for aneuploidy and thus uniparental disomy (UPD). Chromosomes 14 and 15 are imprinted with expression of genes dependent on the parental origin of the chromosome. Correction of a trisomic or monosomic conceptus for chromosomes 14 or 15 would lead to one of the established UPD 14mat/pat or UPD 15 (Prader-Willi/Angelman) syndromes (PWS/AS). In view of this, prenatal UPD testing should be considered for balanced carriers of a ROB, fetuses with a familial or de novo balanced ROB that contains chromosome 14 or 15 or with a normal karyotype when a parent is a carrier of a balanced ROB with a 14 or 15. Individuals with congenital anomalies and an abnormal phenotype and carry a ROB involving the two imprinted chromosomes should also be UPD tested.
PubMed: 26835328
DOI: 10.3978/j.issn.2224-4336.2014.03.03 -
Nature May 2003Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by features reminiscent of marked premature ageing. Here, we present evidence of...
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by features reminiscent of marked premature ageing. Here, we present evidence of mutations in lamin A (LMNA) as the cause of this disorder. The HGPS gene was initially localized to chromosome 1q by observing two cases of uniparental isodisomy of 1q-the inheritance of both copies of this material from one parent-and one case with a 6-megabase paternal interstitial deletion. Sequencing of LMNA, located in this interval and previously implicated in several other heritable disorders, revealed that 18 out of 20 classical cases of HGPS harboured an identical de novo (that is, newly arisen and not inherited) single-base substitution, G608G(GGC > GGT), within exon 11. One additional case was identified with a different substitution within the same codon. Both of these mutations result in activation of a cryptic splice site within exon 11, resulting in production of a protein product that deletes 50 amino acids near the carboxy terminus. Immunofluorescence of HGPS fibroblasts with antibodies directed against lamin A revealed that many cells show visible abnormalities of the nuclear membrane. The discovery of the molecular basis of this disease may shed light on the general phenomenon of human ageing.
Topics: Adult; Aging; Base Sequence; Cell Membrane; Child; Chromosomes, Human, Pair 1; DNA Mutational Analysis; Exons; Female; Fibroblasts; Fluorescent Antibody Technique; Homozygote; Humans; In Situ Hybridization, Fluorescence; Lamin Type A; Male; Pedigree; Point Mutation; Progeria; RNA Splice Sites; Syndrome; Uniparental Disomy
PubMed: 12714972
DOI: 10.1038/nature01629