Maternal mosaicism for IDUA deletion clarifies recurrence risk in MPS I.
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ABSTRACT:
SUBMITTER: Breen C
PROVIDER: S-EPMC5052355 | biostudies-literature | 2016
REPOSITORIES: biostudies-literature
Publications
Maternal mosaicism for <i>IDUA</i> deletion clarifies recurrence risk in MPS I.
Breen Catherine C Mercer Jean J Jones Simon A SA Jahic Amir A Heptinstall Lesley L Tylee Karen K Newman William G WG Beetz Christian C
Human genome variation 20161006
Mucopolysaccharidosis I (MPS I) is a rare autosomal recessive multisystem lysosomal storage disorder. It is caused by biallelic loss-of-function variants in <i>IDUA,</i> encoding alpha-l iduronidase. Here, we describe an individual affected by MPS I due to a paternally inherited deletion of <i>IDUA</i> exons 1 and 2, c.(?_-88)_(299+1_300-1)del and a whole-gene deletion of <i>IDUA</i> (?_-88?)_(*136?)del secondary to maternal somatic mosaicism. We define a previously unreported mutational mechani ...[more]
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Project description:New human mutations are thought to originate in germ cells, thus making a recurrence of the same mutation in a sibling exceedingly rare. However, increasing sensitivity of genomic technologies has anecdotally revealed mosaicism for mutations in somatic tissues of apparently healthy parents. Such somatically mosaic parents might also have germline mosaicism that can potentially cause unexpected intergenerational recurrences. Here, we show that somatic mosaicism for transmitted mutations among parents of children with simplex genetic disease is more common than currently appreciated. Using the sensitivity of individual-specific breakpoint PCR, we prospectively screened 100 families with children affected by genomic disorders due to rare deletion copy-number variants (CNVs) determined to be de novo by clinical analysis of parental DNA. Surprisingly, we identified four cases of low-level somatic mosaicism for the transmitted CNV in DNA isolated from parental blood. Integrated probabilistic modeling of gametogenesis developed in response to our observations predicts that mutations in parental blood increase recurrence risk substantially more than parental mutations confined to the germline. Moreover, despite the fact that maternally transmitted mutations are the minority of alleles, our model suggests that sexual dimorphisms in gametogenesis result in a greater proportion of somatically mosaic transmitting mothers who are thus at increased risk of recurrence. Therefore, somatic mosaicism together with sexual differences in gametogenesis might explain a considerable fraction of unexpected recurrences of X-linked recessive disease. Overall, our results underscore an important role for somatic mosaicism and mitotic replicative mutational mechanisms in transmission genetics.
| S-EPMC4129404 | biostudies-literature
Project description:BackgroundMucopolysaccharidosis type I (MPS I) is a rare, recessively inherited lysosomal storage disorder, characterized by progressive multi-systemic disease. It is caused by a reduced or absent alpha-l iduronidase (IDUA) enzyme activity secondary to biallelic loss-of-function variants in the IDUA. Over 200 causative variants in IDUA have been identified. Nevertheless, there is a fraction of MPS I patients with only a single mutated IDUA allele detectable.MethodsAs genetic testing of MPS I is usually based on sequencing methods, copy number variations (CNVs) in IDUA can be missed and therefore presumably remain underdiagnosed. The aim of this study was the detection of CNVs using an IDUA-specific in house multiplex ligation-dependent probe amplification (MLPA) assay.ResultsA total of five unrelated MPS I patient samples were re-analyzed after only a single heterozygous IDUA mutation c.979G>C (p.A327P), c.1469T>C (p.L490P), c.1598C>G (p.P533R), c.1205G>A (p.W402X), c.973-7C>G (p.?) could be identified. We detected a novel splice site variant c.973-7C>G (p.?), as well as two novel CNVs, a large deletion of IDUA exon 14 and 3'UTR c.(1828 + 1_1829-1)_(*1963_?)del, and a large duplication extending from IDUA exon 2 to intron 12 c.(157 + 1_158-1)_(1727 + 1_1728-1)dup.ConclusionTogether with the CNVs we previously identified, a total of four pathogenic IDUA CNVs have now been reported.
| S-EPMC6732313 | biostudies-literature
Project description:Most new mutations are observed to arise in fathers, and increasing paternal age positively correlates with the risk of new variants. Interestingly, new mutations in X-linked recessive disease show elevated familial recurrence rates. In male offspring, these mutations must be inherited from mothers. We previously developed a simulation model to consider parental mosaicism as a source of transmitted mutations. In this paper, we extend and formalize the model to provide analytical results and flexible formulas. The results implicate parent of origin and parental mosaicism as central variables in recurrence risk. Consistent with empirical data, our model predicts that more transmitted mutations arise in fathers and that this tendency increases as fathers age. Notably, the lack of expansion later in the male germline determines relatively lower variance in the proportion of mutants, which decreases with paternal age. Subsequently, observation of a transmitted mutation has less impact on the expected risk for future offspring. Conversely, for the female germline, which arrests after clonal expansion in early development, variance in the mutant proportion is higher, and observation of a transmitted mutation dramatically increases the expected risk of recurrence in another pregnancy. Parental somatic mosaicism considerably elevates risk for both parents. These findings have important implications for genetic counseling and for understanding patterns of recurrence in transmission genetics. We provide a convenient online tool and source code implementing our analytical results. These tools permit varying the underlying parameters that influence recurrence risk and could be useful for analyzing risk in diverse family structures.
| S-EPMC4185125 | biostudies-literature
Project description:Background Maternal mRNA provisioning of oocytes regulates early embryogenesis. Maternal transcripts are degraded as zygotic genome activation (ZGA) intensifies, a phenomenon known as the maternal-to-zygotic transition (MZT). Here, we examine gene expression over nine developmental stages in the Pacific rice coral, Montipora capitata, from eggs and embryos at 1, 4, 9, 14, 22, and 36 h-post-fertilization (hpf), as well as swimming larvae (9d), and adult colonies. Results Weighted Gene Coexpression Network Analysis revealed four expression peaks, identifying the maternal complement, two waves of the MZT, and adult expression. Gene ontology enrichment revealed maternal mRNAs are dominated by cell division, methylation, biosynthesis, metabolism, and protein/RNA processing and transport functions. The first MZT wave occurs from ~4-14 hpf and is enriched in terms related to biosynthesis, methylation, cell division, and transcription. In contrast, functional enrichment in the second MZT wave, or ZGA, from 22 hpf-9dpf, includes ion/peptide transport and cell signaling. Finally, adult expression is enriched for functions related to signaling, metabolism, and ion/peptide transport. Our proposed MZT timing is further supported by expression of enzymes involved in zygotic transcriptional repression (Kaiso) and activation (Sox2), which peak at 14 hpf and 22 hpf, respectively. Further, DNA methylation writing (DNMT3a) and removing (TET1) enzymes peak and remain stable past ~4 hpf, suggesting that methylome programming occurs before 4 hpf. Conclusions Our high-resolution insight into the coral maternal mRNA and MZT provides essential baseline information to understand parental carryover effects and the sensitivity of developmental success under increasing environmental stress. Supplementary Information The online version contains supplementary material available at 10.1186/s12864-021-08114-y.
| S-EPMC8588723 | biostudies-literature
Project description:OBJECTIVE:De novo mutations contribute significantly to severe early-onset genetic disorders. Even if the mutation is apparently de novo, there is a recurrence risk due to parental germ line mosaicism, depending on in which gonadal generation the mutation occurred. METHODS:We demonstrate the power of using SMRT sequencing and ddPCR to determine parental origin and allele frequencies of de novo mutations in germ cells in two families whom had undergone assisted reproduction. RESULTS:In the first family, a TCOF1 variant c.3156C>T was identified in the proband with Treacher Collins syndrome. The variant affects splicing and was determined to be of paternal origin. It was present in <1% of the paternal germ cells, suggesting a very low recurrence risk. In the second family, the couple had undergone several unsuccessful pregnancies where a de novo mutation PTPN11 c.923A>C causing Noonan syndrome was identified. The variant was present in 40% of the paternal germ cells suggesting a high recurrence risk. CONCLUSIONS:Our findings highlight a successful strategy to identify the parental origin of mutations and to investigate the recurrence risk in couples that have undergone assisted reproduction with an unknown donor or in couples with gonadal mosaicism that will undergo preimplantation genetic diagnosis.
| S-EPMC5725701 | biostudies-literature
Project description:Mucopolysaccharidosis (MPS) type I and II are two closely related lysosomal storage diseases associated with disrupted glycosaminoglycan catabolism. In MPS II, the first step of degradation of heparan sulfate (HS) and dermatan sulfate (DS) is blocked by a deficiency in the lysosomal enzyme iduronate 2-sulfatase (IDS), while, in MPS I, blockage of the second step is caused by a deficiency in iduronidase (IDUA). The subsequent accumulation of HS and DS causes lysosomal hypertrophy and an increase in the number of lysosomes in cells, and impacts cellular functions, like cell adhesion, endocytosis, intracellular trafficking of different molecules, intracellular ionic balance, and inflammation. Characteristic phenotypical manifestations of both MPS I and II include skeletal disease, reflected in short stature, inguinal and umbilical hernias, hydrocephalus, hearing loss, coarse facial features, protruded abdomen with hepatosplenomegaly, and neurological involvement with varying functional concerns. However, a few manifestations are disease-specific, including corneal clouding in MPS I, epidermal manifestations in MPS II, and differences in the severity and nature of behavioral concerns. These phenotypic differences appear to be related to different ratios between DS and HS, and their sulfation levels. MPS I is characterized by higher DS/HS levels and lower sulfation levels, while HS levels dominate over DS levels in MPS II and sulfation levels are higher. The high presence of DS in the cornea and its involvement in the arrangement of collagen fibrils potentially causes corneal clouding to be prevalent in MPS I, but not in MPS II. The differences in neurological involvement may be due to the increased HS levels in MPS II, because of the involvement of HS in neuronal development. Current treatment options for patients with MPS II are often restricted to enzyme replacement therapy (ERT). While ERT has beneficial effects on respiratory and cardiopulmonary function and extends the lifespan of the patients, it does not significantly affect CNS manifestations, probably because the enzyme cannot pass the blood-brain barrier at sufficient levels. Many experimental therapies, therefore, aim at delivery of IDS to the CNS in an attempt to prevent neurocognitive decline in the patients.
| S-EPMC8345985 | biostudies-literature
Project description:Importance:Maternal use of folic acid supplements has been inconsistently associated with reduced risk for autism spectrum disorder (ASD) in the child. No study to date has examined this association in the context of ASD recurrence in high-risk families. Objective:To examine the association between maternal prenatal vitamin use and ASD recurrence risk in younger siblings of children with ASD. Design, Setting, and Participants:This prospective cohort study analyzed data from a sample of children (n?=?332) and their mothers (n?=?305) enrolled in the MARBLES (Markers of Autism Risk in Babies: Learning Early Signs) study. Participants in the MARBLES study were recruited at the MIND Institute of the University of California, Davis and were primarily from families receiving services for children with ASD in the California Department of Developmental Services. In this sample, the younger siblings at high risk for ASD were born between December 1, 2006, and June 30, 2015, and completed a final clinical assessment within 6 months of their third birthday. Prenatal vitamin use during pregnancy was reported by mothers during telephone interviews. Data analysis for this study was conducted from January 1, 2017, to December 3, 2018. Main Outcomes and Measures:Autism spectrum disorder, other nontypical development (non-TD), and typical development (TD) were algorithmically defined according to Autism Diagnostic Observation Schedule and Mullen Scales of Early Learning subscale scores. Results:After exclusions, the final sample comprised 241 younger siblings, of which 140 (58.1%) were male and 101 (41.9%) were female, with a mean (SD) age of 36.5 (1.6) months. Most mothers (231 [95.9%]) reported taking prenatal vitamins during pregnancy, but only 87 mothers (36.1%) met the recommendations to take prenatal vitamins in the 6 months before pregnancy. The prevalence of ASD was 14.1% (18) in children whose mothers took prenatal vitamins in the first month of pregnancy compared with 32.7% (37) in children whose mothers did not take prenatal vitamins during that time. Children whose mothers reported taking prenatal vitamins during the first month of pregnancy were less likely to receive an ASD diagnosis (adjusted relative risk [RR], 0.50; 95% CI, 0.30-0.81) but not a non-TD 36-month outcome (adjusted RR, 1.14; 95% CI, 0.75-1.75) compared with children whose mothers reported not taking prenatal vitamins. Children in the former maternal prenatal vitamin group also had statistically significantly lower autism symptom severity (adjusted estimated difference,?-0.60; 95% CI, -0.97 to -0.23) and higher cognitive scores (adjusted estimated difference,?7.1; 95% CI, 1.2-13.1). Conclusions and Relevance:Maternal prenatal vitamin intake during the first month of pregnancy may reduce ASD recurrence in siblings of children with ASD in high-risk families. Additional research is needed to confirm these results; to investigate dose thresholds, contributing nutrients, and biologic mechanisms of prenatal vitamins; and to inform public health recommendations for ASD prevention in affected families.
| S-EPMC6450282 | biostudies-literature
Project description:The 17q21.31 microdeletion syndrome is characterised by intellectual disability, epilepsy, distinctive facial dysmorphism, and congenital anomalies. To date, all individuals reported with this syndrome have been simplex patients, resulting from de novo deletions. Here, we report sibling recurrence of the 17q21.31 microdeletion syndrome in two independent families. In both families, the mother was confirmed to be the parent-of-origin for the 17q21.31 deletion. Fluorescence in situ hybridisation analyses in buccal mucosa cells, of the mother of family 1, identified monosomy 17q21.31 in 4/50 nuclei (8%). In mother of family 2, the deletion was identified in 2/60 (3%) metaphase and in 3/100 (3%) interphase nuclei in peripheral lymphocytes, and in 7/100 (7%) interphase nuclei in buccal cells. A common 17q21.31 inversion polymorphism predisposes to non-allelic homologous recombination and hereby to the 17q21.31 microdeletion syndrome. On the basis of the 17q21.31 inversion status of the parents, we calculated that the probability of the second deletion occurring by chance alone was 1/14,438 and 1/4812, respectively. If the inversion status of the parents of a child with the 17q21.31 microdeletion syndrome is unknown, the overall risk of a second child with the 17q21.31 microdeletion is 1/9461. We conclude that the presence of low-level maternal somatic-gonadal mosaicism is associated with the microdeletion recurrence in these families. This suggests that the recurrence risk for parents with a child with a 17q21.31 microdeletion for future pregnancies is higher than by chance alone and testing for mosaicism in the parents might be considered as a helpful tool in the genetic counselling.
| S-EPMC3376266 | biostudies-literature
Project description:BackgroundMucopolysaccharidosis type I (MPS-I) is a lysosomal storage disorder caused by a deficiency of the enzyme α-l-iduronidase, leading to accumulation of undegraded dermatan and heparan sulfates in the cells and secondary multiorgan dysfunction. In humans, depending upon the nature of the underlying mutation(s) in the IDUA gene, the condition presents with a spectrum of clinical severity.ObjectivesTo characterize the clinical and biochemical phenotypes, and the genotype of a family of Golden Retriever dogs.AnimalsTwo affected siblings and 11 related dogs.MethodsFamily study. Urine metabolic screening and leucocyte lysosomal enzyme activity assays were performed for biochemical characterization. Whole genome sequencing was used to identify the causal mutation.ResultsThe clinical signs shown by the proband resemble the human attenuated form of the disease, with a dysmorphic appearance, musculoskeletal, ocular and cardiac defects, and survival to adulthood. Urinary metabolic studies identified high levels of dermatan sulfate, heparan sulfate, and heparin. Lysosomal enzyme activities demonstrated deficiency in α-l-iduronidase activity in leucocytes. Genome sequencing revealed a novel homozygous deletion of 287 bp resulting in full deletion of exon 10 of the IDUA gene (NC_006585.3(NM_001313883.1):c.1400-76_1521+89del). Treatment with pentosan polyphosphate improved the clinical signs until euthanasia at 4.5 years.Conclusion and clinical importanceAnalysis of the genotype/phenotype correlation in this dog family suggests that dogs with MPS-I could have a less severe phenotype than humans, even in the presence of severe mutations. Treatment with pentosan polyphosphate should be considered in dogs with MPS-I.
| S-EPMC7517864 | biostudies-literature
Project description:Mutations in the FBN1 gene cause Marfan syndrome (MFS), a dominantly inherited connective tissue disease. Almost all the identified FBN1mutations have been family specific, and the rate of new mutations is high. We report here a de novo FBN1mutation that was identified in two sisters with MFS born to clinically unaffected parents. The paternity and maternity were unequivocally confirmed by genotyping. Although one of the parents had to be an obligatory carrier for the mutation, we could not detect the mutation in the leukocyte DNA of either parent. To identify which parent was a mosaic for the mutation we analyzed several tissues from both parents, with a quantitative and sensitive solid-phase minisequencing method. The mutation was not, however, detectable in any of the analyzed tissues. Although the mutation could not be identified in a sperm sample from the father or in samples of multiple tissue from the mother, we concluded that the mother was the likely mosaic parent and that the mutation must have occurred during the early development of her germ-line cells. Mosaicism confined to germ-line cells has rarely been reported, and this report of mosaicism for the FBN1 mutation in MFS represents an important case, in light of the evaluation of the recurrence risk in genetic counseling of families with MFS.
| S-EPMC1377823 | biostudies-other