The phenotypic variations of multi-locus imprinting disturbances associated with maternal-effect variants of NLRP5 range from overt imprinting disorder to apparently healthy phenotype

Abstract Background A subset of individuals affected by imprinting disorders displays multi-locus imprinting disturbances (MLID). MLID has been associated with maternal-effect variants that alter the maintenance of methylation at germline-derived differentially methylated regions (gDMRs) in early embryogenesis. Pedigrees of individuals with MLID also include siblings with healthy phenotype. However, it is unknown if these healthy individuals have MLID themselves or if their methylation patterns differ from those associated with imprinting disorders, and in general, if MLID affects the clinical phenotype. Methods We have investigated gDMR methylation by locus-specific and whole-genome analyses in a family with multiple pregnancy losses, a child with Beckwith-Wiedemann syndrome (BWS) and a further child with no clinical diagnosis of imprinting disorder or other pathologies. Results We detected MLID with different methylation profiles in the BWS-affected and healthy siblings. Whole-exome sequencing demonstrated the presence of novel loss-of-function variants of NLRP5 in compound heterozygosity in the mother. The methylation profiles of the two siblings were compared with those of other cases with MLID and control groups by principal component analysis and unsupervised hierarchical clustering, but while their patterns were clearly separated from those of controls, we were unable to cluster those associated with specific clinical phenotypes among the MLID cases. Conclusion The identification of two novel maternal-effect variants of NLRP5 associated with poly-abortivity and MLID adds further evidence to the role of this gene in the maintenance of genomic imprinting in early embryos. Furthermore, our results demonstrate that within these pedigrees, MLID can also be present in the progeny with healthy phenotype, indicating that some sort of compensation occurs between altered imprinted loci in these individuals. The analysis of larger cohorts of patients with MLID is needed to formulate more accurate epigenotype-phenotype correlations.

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Loss-of-function maternal-effect mutations of PADI6 are associated with familial and sporadic Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance

Clinical Epigenetics ◽

10.1186/s13148-020-00925-2 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Maria Vittoria Cubellis ◽

Laura Pignata ◽

Ankit Verma ◽

Angela Sparago ◽

Rosita Del Prete ◽

...

Keyword(s):

Maternal Effect ◽

Hydatidiform Mole ◽

In Silico Analysis ◽

Recurrence Risk ◽

Early Embryo ◽

Dominant Negative ◽

Sequencing Analysis ◽

Loss Of Function ◽

Imprinting Disorders ◽

Whole Exome

Abstract Background PADI6 is a component of the subcortical maternal complex, a group of proteins that is abundantly expressed in the oocyte cytoplasm, but is required for the correct development of early embryo. Maternal-effect variants of the subcortical maternal complex proteins are associated with heterogeneous diseases, including female infertility, hydatidiform mole, and imprinting disorders with multi-locus imprinting disturbance. While the involvement of PADI6 in infertility is well demonstrated, its role in imprinting disorders is less well established. Results We have identified by whole-exome sequencing analysis four cases of Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance whose mothers are carriers of PADI6 variants. In silico analysis indicates that these variants result in loss of function, and segregation analysis suggests they act as either recessive or dominant-negative maternal-effect mutations. Genome-wide methylation analysis revealed heterogeneous and extensively altered methylation profiles of imprinted loci in the patients, including two affected sisters, but not in their healthy siblings. Conclusion Our results firmly establish the role of PADI6 in imprinting disorders. We report loss-of-function maternal-effect variants of PADI6 that are associated with heterogeneous multi-locus imprinting disturbances in the progeny. The rare finding of two siblings affected by Beckwith-Wiedemann syndrome suggests that in some cases, familial recurrence risk of these variants may be high. However, the heterogeneous phenotypes of the other pedigrees suggest that altered oocyte PADI6 function results in stochastic maintenance of methylation imprinting with unpredictable consequences on early embryo health.

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Maternal variants in NLRP and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring

Journal of Medical Genetics ◽

10.1136/jmedgenet-2017-105190 ◽

2018 ◽

Vol 55 (7) ◽

pp. 497-504 ◽

Cited By ~ 38

Author(s):

Matthias Begemann ◽

Faisal I Rezwan ◽

Jasmin Beygo ◽

Louise E Docherty ◽

Julia Kolarova ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Maternal Effect ◽

Pregnancy Loss ◽

Early Embryo ◽

Imprinting Disorders ◽

Monozygotic Twinning ◽

Whole Exome ◽

Maternal Effect Genes ◽

Mammalian Genes

BackgroundGenomic imprinting results from the resistance of germline epigenetic marks to reprogramming in the early embryo for a small number of mammalian genes. Genetic, epigenetic or environmental insults that prevent imprints from evading reprogramming may result in imprinting disorders, which impact growth, development, behaviour and metabolism. We aimed to identify genetic defects causing imprinting disorders by whole-exome sequencing in families with one or more members affected by multilocus imprinting disturbance.MethodsWhole-exome sequencing was performed in 38 pedigrees where probands had multilocus imprinting disturbance, in five of whom maternal variants in NLRP5 have previously been found.ResultsWe now report 15 further pedigrees in which offspring had disturbance of imprinting, while their mothers had rare, predicted-deleterious variants in maternal effect genes, including NLRP2, NLRP7 and PADI6. As well as clinical features of well-recognised imprinting disorders, some offspring had additional features including developmental delay, behavioural problems and discordant monozygotic twinning, while some mothers had reproductive problems including pregnancy loss.ConclusionThe identification of 20 putative maternal effect variants in 38 families affected by multilocus imprinting disorders adds to the evidence that maternal genetic factors affect oocyte fitness and thus offspring development. Testing for maternal-effect genetic variants should be considered in families affected by atypical imprinting disorders.

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Kindler's Syndrome with Recurrent Neutropenia: Report of Two Cases from Saudi Arabia

Journal of Pediatric Genetics ◽

10.1055/s-0040-1721077 ◽

2020 ◽

Author(s):

Yousef Binamer ◽

Muzamil A. Chisti

Keyword(s):

Autosomal Recessive ◽

Common Mechanism ◽

Sequencing Analysis ◽

Loss Of Function ◽

Skin Atrophy ◽

Whole Exome ◽

Infancy And Childhood ◽

Genetics And Genomics ◽

New Feature ◽

Generation Sequencing

AbstractKindler syndrome (KS) is a rare photosensitivity disorder with autosomal recessive mode of inheritance. It is characterized by acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. Besides these major features, many minor presentations have also been reported in the literature. We are reporting two cases with atypical features of the syndrome and a new feature of recurrent neutropenia. Whole exome sequencing analysis was done using next-generation sequencing which detected a homozygous loss-of-function (LOF) variant of FERMT1 in both patients. The variant is classified as a pathogenic variant as per the American College of Medical Genetics and Genomics guidelines. Homozygous LOF variants of FERMT1 are a common mechanism of KS and as such confirm the diagnosis of KS in our patients even though the presentation was atypical.

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Autosomal Recessive Non-syndromic Keratoconus: Homozygous Frameshift Variant in the Candidate Novel Gene GALNT14

Current Molecular Medicine ◽

10.2174/1566524019666190730095630 ◽

2019 ◽

Vol 19 (9) ◽

pp. 683-687 ◽

Cited By ~ 3

Author(s):

Tawfiq Froukh ◽

Ammar Hawwari

Keyword(s):

Strong Evidence ◽

Autosomal Recessive ◽

Eye Diseases ◽

Initial Reaction ◽

Genetic Contribution ◽

Loss Of Function ◽

Consanguineous Family ◽

Truncated Protein ◽

Threonine Residue ◽

Whole Exome

Background: Keratoconus (KC) is usually bilateral, noninflammatory progressive corneal ectasia in which the cornea becomes progressively thin and conical. Despite the strong evidence of genetic contribution in KC, the etiology of KC is not understood in most cases. Methods: In this study, we used whole-exome sequencing to identify the genetic cause of KC in two sibs in a consanguineous family. The Homozygous frameshift variant NM_001253826.1:c.60delC;p.Leu21Cysfs*6 was identified in the gene Nacetylgalactosaminyltransferase 14 (GALNT14). The variant does not exist in all public databases neither in our internal exome database. Moreover, no database harbours homozygous loss of function variants in the candidate gene. Result: GALNT14 catalyses the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D- galactosamine residue to a serine or threonine residue on target proteins especially Mucins. Conclusion: As alterations of mucin’s glycosylation are linked to a number of eye diseases, we demonstrate in this study an association between the truncated protein GALNT14 and KC.

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UPLC-Q-TOF/MS based Untargeted Metabolite and Lipid Analysis on Premature Ovarian Insufficiency Plasma Samples.

Current Pharmaceutical Analysis ◽

10.2174/1573412916666200102112339 ◽

2020 ◽

Vol 16 ◽

Author(s):

Yasemin Taşcı ◽

Rahime Bedir Fındık ◽

Meryem Kuru Pekcan ◽

Ozan Kaplan ◽

Mustafa Çelebier

Keyword(s):

Lipid Analysis ◽

Principal Component ◽

Premature Ovarian Insufficiency ◽

Plasma Samples ◽

Ovarian Insufficiency ◽

Analytical Methodology ◽

Drug Molecules ◽

New Treatment ◽

And Control ◽

Phenyl Alanine

Background: Metabolomics is one of the main areas to understand cellular process at molecular level by analyzing metabolites. In recent years metabolomics has been emerged as key tool to understand molecular basis of disease, find diagnostic and prognostic biomarkers, and develop new treatment opportunities and drug molecules. Objective: In this study, an untargeted metabolite and lipid analysis were performed to identify potential biomarkers on premature ovarian insufficiency plasma samples. 43 POI subject plasma samples were compared with 32 healthy subject plasma samples. Methods: Plasma samples were pooled and extracted using chloroform:methanol:water (3:3:1 v/v/v) mixture. Agilent 6530 LC/MS Q-TOF instrument equipped with ESI source was used for analysis. A C18 column (Agilent Zorbax 1.8 μM, 50 x 2.1 mm) was used for separation of metabolites and lipids. XCMS, an “R software” based freeware program, was used for peak picking, grouping and comparing the findings. Isotopologue Parameter Optimization (IPO) software was used in order to optimize XCMS parameters. The analytical methodology and data mining process were validated according to the literature. Results: 83 metabolite peaks and 213 lipid peaks were found to be in semi-quantitatively and statistically different (fold change >1.5, p <0.05) between the POI plasma samples and control subjects. Conclusion: According to the results, two groups were successfully separated through principal component analysis. Among the peaks, phenyl alanine, decanoyl-L-carnitine, 1-palmitoyllysophosphatidylcholine and PC(O-16:0/2:0) were identified through auto MS/MS and matched with human metabolome database and proposed as plasma biomarker for POI and monitoring the patients in treatment period.

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The Mutation masculinizer (man) Defines a Sex-Determining Gene With Maternal and Zygotic Functions in Musca domestica L.

Genetics ◽

10.1093/genetics/145.1.173 ◽

1997 ◽

Vol 145 (1) ◽

pp. 173-183 ◽

Cited By ~ 1

Author(s):

R Schmidt ◽

M Hediger ◽

R Nöthiger ◽

A Dübendorfer

Keyword(s):

Musca Domestica ◽

Maternal Effect ◽

Dominant Factor ◽

Loss Of Function ◽

New Mutation ◽

Yolk Proteins ◽

Hypomorphic Allele ◽

Internal Structures ◽

Primary Signal ◽

Pole Cells

In Musca domestica, the primary signal for sex determination is the dominant factor M, which is assumed to regulate a postulated female-determining gene F. Presence of M prevents expression of F so that male development ensues. In the absence of M, F can become active, which dictates the female pathway. The existence of F is inferred from FD, a dominant factor that is epistatic to M. We describe a new mutation masculinizer, which has all the properties expected for a null or strongly hypomorphic allele of F: (1) it maps to the same chromosomal location as FD, (2) homozygous man/man animals develop as males, (3) homozygous man/man clones generated in man/+ female larvae differentiate male structures, (4) man has a sex-determining maternal effect. About a third of the morphological males synthesize yolk proteins, which indicates that they are intersexual in internal structures. The maternal effect of man is complete in offspring that derive from homozygous man/man pole cells transplanted into female hosts. In this case, all man/+ progeny become fertile males that do not produce yolk proteins. A sex-determining maternal effect has previously been demonstrated for FD. Like F, maternal man + is needed for zygotic man + to become active, providing further evidence that man is a loss-of-function allele of F.

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Identification of a novel homozygous loss-of-function mutation in FUCA1 gene causing severe fucosidosis: A case report

Journal of International Medical Research ◽

10.1177/03000605211005975 ◽

2021 ◽

Vol 49 (4) ◽

pp. 030006052110059

Author(s):

Xinwen Zhang ◽

Shaozhi Zhao ◽

Hongwei Liu ◽

Xiaoyan Wang ◽

Xiaolei Wang ◽

...

Keyword(s):

Amino Acids ◽

Lysosomal Storage Disorder ◽

Autosomal Recessive ◽

Signs And Symptoms ◽

Lysosomal Storage ◽

Loss Of Function ◽

Wild Type ◽

Single Nucleotide ◽

Whole Exome ◽

Exon 1

Fucosidosis is a rare lysosomal storage disorder characterized by deficiency of α-L-fucosidase with an autosomal recessive mode of inheritance. Here, we describe a 4-year-old Chinese boy with signs and symptoms of fucosidosis but his parents were phenotypically normal. Whole exome sequencing (WES) identified a novel homozygous single nucleotide deletion (c.82delG) in the exon 1 of the FUCA1 gene. This mutation will lead to a frameshift which will result in the formation of a truncated FUCA1 protein (p.Val28Cysfs*105) of 132 amino acids approximately one-third the size of the wild type FUCA1 protein (466 amino acids). Both parents were carrying the mutation in a heterozygous state. This study expands the mutational spectrum of the FUCA1 gene associated with fucosidosis and emphasises the benefits of WES for accurate and timely clinical diagnosis of this rare disease.

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AB0994 NEW ALTERNATIVE IN THE TREATMENT OF PATIENT WITH MUTATION OF GEN LACC1

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5555 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1790.2-1790

Author(s):

R. M. Alcobendas ◽

C. Quintana ◽

J. Arostegui ◽

C. Udaondo ◽

S. Murias Loza ◽

...

Keyword(s):

Chart Review ◽

Loss Of Function ◽

Acute Phase Reactants ◽

Reactive Protein ◽

Inflammatory Parameters ◽

Whole Exome ◽

Multiple Treatments ◽

Clinical Chart ◽

Clinical Worsening

Background:Few patients have been described in the literature with mutations in the Lacasa Domain containing one (LACC1) gene. Its clinical presentation usually associates sustained systemic inflammation associated with chronic polyarticular erosive arthritis. Until now, there have been multiple treatments described to try to control the disease, however, they are generally unsuccessful in the long term.Objectives:Describe the clinical course of a patient as well as the different treatments usedMethods:Clinical chart reviewResults:Female 18-year-old born from a consanguineous Moroccan couple. Mother, brother and sister with similar conditions. She started at 3 years with fever, anemia, intense elevation of acute phase reactants and symmetric polyarthritis (knees, elbows, carps, shoulders, hands and ankles). Subsequent whole exome sequencing identified c.128_129delGT mutation in the LACC1/FAMIN gene. During the course of her illness, she has received treatment with oral, intravenous and infiltrated corticosteroid, methotrexate and etanercept, without getting adequate control of the disease. In 2016, she started treatment with tocilizumab (8 mg / kg every two weeks), obtaining an acceptable control of the disease (requiring periodic infiltrations every 2-3 months due to persistent arthritis). Nonetheless, in April 2019, she consulted for clinical worsening of the arthritis and laboratory test (C reactive protein 99.7 mg / L, erythrosedimentation rate 53 mm / h, leukocytes 13,500/µL and neutrophils 10,930/µL). At that time, she discontinued therapy with tocilizumab and started tofacitinib 5 mg every 12 hours with good evolution. Since its introduction, it has not required joint infiltration again and the inflammatory parameters (persistently elevated previously) have normalized.Conclusion:The jak kinasa inhibitors may be a treatment option in those patients with bad response to conventional therapy.References:[1]Rabionet R, Remesal A, Mensa-Vilaró A, Murías S, Alcobendas R, González-Roca E, Ruiz-Ortiz E, Antón J, Iglesias E, Modesto C, Comas D, Puig A, Drechsel O, Ossowski S, Yagüe J, Merino R, Estivill X, Arostegui JI. Biallelic loss-of-function LACC1/FAMIN Mutations Presenting as Rheumatoid Factor-Negative Polyarticular Juvenile Idiopathic Arthritis. Sci Rep. 2019 Mar 14;9(1):4579Disclosure of Interests:None declared

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Variable Expressivity of the Beckwith-Wiedemann Syndrome in Four Pedigrees Segregating Loss-of-Function Variants of CDKN1C

Genes ◽

10.3390/genes12050706 ◽

2021 ◽

Vol 12 (5) ◽

pp. 706

Author(s):

Angela Sparago ◽

Flavia Cerrato ◽

Laura Pignata ◽

Francisco Cammarata-Scalisi ◽

Livia Garavelli ◽

...

Keyword(s):

Cellular Proliferation ◽

Missense Variant ◽

Abdominal Wall Defects ◽

Loss Of Function ◽

Nonsense Mutations ◽

Molecular Defects ◽

Variable Expressivity ◽

Imprinting Disorder ◽

Perinatal Lethality ◽

Intrafamilial Variability

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by prenatal and/or postnatal overgrowth, organomegaly, abdominal wall defects and tumor predisposition. CDKN1C is a maternally expressed gene of the 11p15.5 chromosomal region and is regulated by the imprinting control region IC2. It negatively controls cellular proliferation, and its expression or activity are frequently reduced in BWS. In particular, loss of IC2 methylation is associated with CDKN1C silencing in the majority of sporadic BWS cases, and maternally inherited loss-of-function variants of CDKN1C are the most frequent molecular defects of familial BWS. We have identified, using Sanger sequencing, novel CDKN1C variants in three families with recurrent cases of BWS, and a previously reported variant in a woman with recurrent miscarriages with exomphalos. Clinical evaluation of the patients showed variable manifestation of the disease. The frameshift and nonsense variants were consistently associated with exomphalos, while the missense variant caused a less severe phenotype. Pregnancy loss and perinatal lethality were found in the families segregating nonsense mutations. Intrafamilial variability of the clinical BWS features was observed, even between siblings. Our data are indicative of severe BWS phenotypes that, with variable expressivity, may be associated with both frameshift and nonsense variants of CDKN1C.

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An Introduction to Development of Centralized and Distributed Stochastic Approximation Algorithm with Expanding Truncations

Algorithms ◽

10.3390/a14060174 ◽

2021 ◽

Vol 14 (6) ◽

pp. 174

Author(s):

Wenxiao Zhao

Keyword(s):

Approximation Algorithm ◽

Stochastic Approximation ◽

Probabilistic Method ◽

Principal Component ◽

Stochastic Approximation Algorithm ◽

The Past ◽

Systems And Control ◽

Ode Method ◽

Centralized Algorithm ◽

And Control

The stochastic approximation algorithm (SAA), starting from the pioneer work by Robbins and Monro in 1950s, has been successfully applied in systems and control, statistics, machine learning, and so forth. In this paper, we will review the development of SAA in China, to be specific, the stochastic approximation algorithm with expanding truncations (SAAWET) developed by Han-Fu Chen and his colleagues during the past 35 years. We first review the historical development for the centralized algorithm including the probabilistic method (PM) and the ordinary differential equation (ODE) method for SAA and the trajectory-subsequence method for SAAWET. Then, we will give an application example of SAAWET to the recursive principal component analysis. We will also introduce the recent progress on SAAWET in a networked and distributed setting, named the distributed SAAWET (DSAAWET).

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