Severe and mild von Willebrand disease in non-consanguineous dizygotic twins - The result of two novel mutations.
0
Citation
0
Reference
10
Related Paper
Keywords:
Dizygotic twins
von Willebrand Disease
Cite
Analysis of concordancy rates in monozygotic and dizygotic twins with Parkinson's disease (PD) has been an important subject for research into the disorder1 and discordancy between twins has traditionally been interpreted as evidence against a genetic etiology of disease. Discordancy in late-onset diseases such as PD is complicated by the possibility that the disease onset may vary considerably between twins, and cases with up to 20 years of discordance have been reported.2 Leucine-rich repeat-kinase type 2 (LRRK2) mutations are the most common Mendelian cause of PD,3, 4 with the G2109S mutation occurring in 1% to 2% of idiopathic cases in the UK.5 Here we report the identification of a pair of identical twins with this mutation who are discordant by more than 10 years. The twins, of English descent, are 70+ years old and were self-reported as identical. The proband developed the first symptoms of PD at age 60 years, with unilateral bradykinesia, rigidity, and rest tremor that became bilateral. The initial good response to levodopa therapy was followed in 5 years by development of motor fluctuations with wearing off, on-off effects, and peak dose and diphasic dyskinesias. The family had autosomal dominant inheritance of PD with a parent and 2 second-degree relatives affected by the disorder. On exam, the twin had a normal smell test and no signs of neurodegenerative disorder. DNA from the proband was sequenced as part of the clinical workup and the heterozygous LRRK2 G2109S mutation was identified. DNA from the twin was sequenced and the mutation was confirmed in the sample. DNA from both twins was run on genomewide arrays (Illumina 660) to confirm that the twins were identical; this also revealed no major chromosomal abnormalities in either twin. These data show that considerable variance in the penetrance of the mutation can occur even in the context of genetic identity. This suggests that the effects of other genetic loci in modifying the age at onset of disease must be minimal and, therefore, that identifying such loci through linkage or association methods will be extremely challenging because the variability in onset age between LRRK2 mutation carriers6 must be largely nongenetic in etiology. Identifying environmental risk factors for disease is notoriously difficult and there is nothing in the personal or medical histories of these twins that provides obvious clues for the reasons behind the current discordance. Indeed, both twins have had similar life courses. The recent data implicating pathology spread in PD is consistent with the notion that the disease process can start at a single site.7 If this is the case, then a stochastic initiation of disease may underlie the discordance as it may for prion disease.8, 9 For reasons of confidentiality minimal clinical details are presented. For further information please contact A.J.L. The funding organizations had no part in the study design or the writing up of this work. Author Roles: GX carried out the laboratory work, AS helped with the interpretation of the array data, LSM interviewed the proband and reviewed the ethical compliance, HH and JH obtained funds for the work, JH drafted the manuscript which all authors reviewed. AJL identified the patient and initiated the study. Financial Disclosures: JH is on Scientific Advisory Boards for Eisai and Merck Serono. AL is on Advisory Boards for Novartis. Teva, Meda, Boehringer Ingelheim, GSK, lpsen, Lundbeck, Allergan. Orion, BIAL, Noscira and Roche. None of the other authors have consultancy or advisory roles. Author Roles: GX carried out the laboratory work, AS helped with the interpretation of the array data, LSM interviewed the proband and reviewed the ethical compliance, HH and JH obtained funds for the work, JH drafted the manuscript which all authors reviewed. AJL identified the patient and initiated the study. Financial Disclosures: JH is on Scientific Advisory Boards for Eisai and Merck Serono. AL is on Advisory Boards for Novartis. Teva, Meda, Boehringer Ingelheim, GSK, lpsen, Lundbeck, Allergan. Orion, BIAL, Noscira and Roche. None of the other authors have consultancy or advisory roles. Georgia Xiromerisiou MD, PhD*, Henry Houlden PhD, MRCP*, Anna Sailer MD*, Laura Silveira-Moriyama MD, PhD*, John Hardy PhD*, Andrew J. Lees MD, FRCP*, * Reta Lila Weston Institute of Neurological Studies and Research Laboratories, Departments of Molecular Neuroscience and of Clinical Neuroscience, University College London (UCL) Institute of Neurology, Queen Square, London, UK.
Proband
LRRK2
Cite
Citations (20)
Cerebellar ataxia
Cite
Citations (9)
MTHFR gene polymorphism regulate folate metabolism, required for normal development of central nervous system and any error in metabolism either due to hereditary or sporadic gene mutation in the family lead to the development of mental retardation in heterozygous condition. In the present study the five families having severe congenital mental retardation was evaluated for C677T genotype variations i.e. CC, CT & TT in probands, mother & father using PCR-RFLP analysis. Highest frequency (60%) was observed in heterozygous condition in the mother of proband. Statistical analysis showing significant difference (p=0.024) were observed in the father of the proband. Interestingly, the insertion of 68bp of CβS gene mutation was also observed in father of one family suggesting paternal or maternal factors influencing for severe mental retardation in children of consanguineous families as an independent risk factor. However, the high degree of genetic heterogeneity is quite striking because of severe mutation in two families. The pedigree analysis showing that the severity of disease transmission probably due to the penetrance of gene and their mode of inheritance is autosomal recessive in nature.
Cite
Citations (6)
Monozygotic twin
Clinical phenotype
Identical twins
Gaucher's disease
Cite
Citations (61)
Autosomal dominant polycystic kidney disease (ADPKD) is the most common single gene disorder resulting in renal failure. It is generally an adult onset disease, but rarely, cases of severe childhood polycystic disease arise in ADPKD families. The clear clinical anticipation in these pedigrees has led to the suggestion that the mutation may be an unstable trinucleotide repeat. We have now identified a nonsense mutation, Tyr3818Stop, in one such family (P117) within the major ADPKD gene, polycystic kidney disease 1 (PKD1). The mutation is shown to be a de novo change in the father, and of grandpaternal origin. PKD1 manifests as typical adult onset disease in the father, but is seen as severe disease, detected as enlarged polycystic kidneys in utero, in one of a pair of dizygotic twins; the other twin has the mutation but no evidence of cysts, consistent with an adult onset disease course. The finding of the same stable mutation associated with very different disease severity in this family indicates that phenotypic variation in PKD1 is not due to a dynamic mutation. It seems most likely that a small number of modifying factors may radically affect the course of disease in PKD1; identification of such factors will have important prognostic implications in this disorder.
PKD1
Nonsense mutation
Anticipation (artificial intelligence)
Pedigree chart
Cite
Citations (102)
Menkes disease (MD) is a rare X‐linked recessive disorder caused by mutations in the ATP7A gene. This neurodegenerative disorder typically affects males and is characterized by impaired copper distribution and the malfunction of several copper‐dependent enzymes. We report clinically discordant female monozygotic twins (MZT) with a heterozygous ATP7A mutation. One twin girl is healthy at the current age of 4 years, whereas the other twin girl developed classical MD, showed disease stabilization under copper histidine treatment but died at the age of 3 years. Presumably, the affected girl developed MD due to skewed X inactivation, although this could not be demonstrated in two tissues (blood, buccal mucosa). This case is a rare example of an affected girl with MD and shows the possibility of a discordant phenotype in MZT girls. As speculated in other X‐linked diseases, the process of monozygotic twinning may be associated with skewed X inactivation leading to a discordant phenotype. © 2015 Wiley Periodicals, Inc.
Menkes disease
Monozygotic twin
Clinical phenotype
Cite
Citations (7)
Discordant expression of Familial Amyloid Neuropathy (FAP) in monozygotic twins is a rare event. Only five such cases have been described in the literature so far. We report the clinical, neurophysiologic and autonomic findings of Brazilian monozygotic twins discordant for the expression of FAP type I. Twin I first presented symptoms at the age of 21, when his brother was completely asymptomatic. Twin 2 only presented symptoms at the age of 25, almost four years after his brother. Both brothers eventually developed the complete phenotype of FAP type I. The occurrence of monozygotic twins discordant for the expression of FAP type I suggests that other factors beside TTR gene mutations should play an important role in the pathogenesis of this condition. Environmental factors, as well as modifier genetic loci are likely to modulate the expression of FAP type I and the study of cases such as the one presented here may help to identify some of these factors.
Monozygotic twin
Pathogenesis
Variable Expression
Amyloid polyneuropathy
Asymptomatic carrier
Cite
Citations (18)
Objective
This study presents the neurologic phenotypes of 2 brothers with a novel homozygous COL4A1 mutation that was identified in a large Turkish consanguineous cohort of neurogenetic diseases.Methods
Whole-exome sequencing and bioinformatic analysis of consanguineous families with children affected by early-onset, neurogenetic disorders was performed using the RD-Connect Genome-Phenome Analysis Platform. We also performed clinical, EEG, and neuroimaging analyses in unaffected siblings and parents.Results
We have identified a homozygous missense mutation in COL4A1 (p.Gly1278Ser, NM_001845.5:c.3832G>T) in 2 siblings affected by small vessel brain disease with periventricular leukoencephalopathy and ocular defects. Presenting symptoms included mild weakness, hemiparetic gait, pyramidal findings, and seizures, whereas their intellectual and behavioral functions were normal. Both parents and 5 of the siblings (3 boys and 2 girls) were heterozygous for the variant. They did not show any clinical or laboratory signs of small vessel disease.Conclusions
COL4A1 has previously been associated with dominant small vessel disease of the brain and other organs, manifesting with high penetrance in heterozygous mutation carriers. Our findings provide evidence that COL4A1-related encephalopathy can be inherited in an autosomal recessive manner, which is important for counseling, prognosis, and treatment. Genotype-phenotype correlations remain to be established.Penetrance
Disease gene identification
Compound heterozygosity
Global developmental delay
Cite
Citations (11)
Monogenic forms of diabetes may account for 1-5% of all cases of diabetes, and may occur in the context of syndromic presentations. We investigated the case of a girl affected by insulin-dependent diabetes, diagnosed at 6 years old, associated with congenital cataract. Her consanguineous parents and her four other siblings did not have diabetes or cataract, suggesting a recessive syndrome. Using whole exome sequencing of the affected proband, we identified a heterozygous p.R825Q ABCC8 mutation, located at the exact same amino-acid position as the p.R825W recurring diabetes mutation, hence likely responsible for the diabetes condition, and a homozygous p.G71S mutation in CRYBB1, a gene known to be responsible for congenital cataract. Both mutations were predicted to be damaging and were absent or extremely rare in public databases. Unexpectedly, we found that the mother was also homozygous for the CRYBB1 mutation, and both the mother and one unaffected sibling were heterozygous for the ABCC8 mutation, suggesting incomplete penetrance of both mutations. Incomplete penetrance of ABCC8 mutations is well documented, but this is the first report of an incomplete penetrance of a CRYBB1 mutation, manifesting between susceptible subjects (unaffected mother vs. affected child) and to some extent within the patient herself, who had distinct cataract severities in both eyes. Our finding illustrates the importance of family studies to unmask the role of confounding factors such as double-gene mutations and incomplete penetrance that may mimic monogenic syndromes including in the case of strongly evocative family structure with consanguinity.
Penetrance
Proband
Cite
Citations (9)
Abstract This study is a clinical report on twin females affected by primary microcephaly who displayed at molecular analysis of heterozygous novel MCPH1 variant. The twins at the age of 10 years developed, in coincidental time, a diagnosis of autoimmune juvenile thyroiditis. The main clinical features presented by the twins consisted of primary microcephaly with occipitofrontal circumference measuring −2 or −3 standard deviation, facial dysmorphism, typical nonsyndromic microcephaly, and mild intellectual disability. Molecular analysis of the major genes involved in primary microcephaly was performed and the following result was found in the twins: MCPH1; chr8.6357416; c.2180 C > T (rs 199861426), p.Pro727. Leu; heterozygous; missense; variant of uncertain significance (class 3). At the age of 10 years, the twins started to have, in coincidental time, marked asthenia and episodes of emotiveness, and laboratory exams disclosed a high level of antithyroid peroxidase leading to the diagnosis of autoimmune juvenile thyroiditis with normal thyroid function. The novel heterozygous MCPH1 variant found in the twins may be directly or indirectly involved in the onset of the primary microcephaly. The thyroid disorder in the twins and its onset, in a coincidental time, confirmed the effect of genetic predisposition on the pathogenesis of the immune thyroiditis.
Microcephaly
Compound heterozygosity
Thyroid peroxidase
Congenital hypothyroidism
Cite
Citations (6)