Correction to: Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG).
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ABSTRACT:
SUBMITTER: Gregg AR
PROVIDER: S-EPMC8776567 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Pathogenic variants in the CFTR gene are causative of classic cystic fibrosis (CF) as well as some nonclassic CF phenotypes. In 2001, CF became the first target of pan-ethnic universal carrier screening by molecular methods. The American College of Medical Genetics and Genomics (ACMG) recommended a core panel of 23 disease-causing variants as the minimal set to be included in pan-ethnic carrier screening of individuals with no family history of the disease, and these variants were usually assessed using targeted methods. The original recommendation also left open the option for laboratories to offer expanded CFTR variant panels; however, at the time, expanded CFTR variant panels were met with some controversy on the basis of the available technologies and the limited phenotypic knowledge of rare variants. Both of those aspects have now evolved, prompting this update of the ACMG technical standards for CFTR variant testing.
| S-EPMC8268680 | biostudies-literature
Project description:PurposeChromosomal microarray (CMA) is recommended as the first-tier test in evaluation of individuals with neurodevelopmental disability and congenital anomalies. CMA may not detect balanced cytogenomic abnormalities or uniparental disomy (UPD), and deletion/duplications and regions of homozygosity may require additional testing to clarify the mechanism and inform accurate counseling. We conducted an evidence review to synthesize data regarding the benefit of additional testing after CMA to inform a genetic diagnosis.MethodsThe review was guided by key questions related to the detection of genomic events that may require additional testing. A PubMed search for original research articles, systematic reviews, and meta-analyses was evaluated from articles published between 1 January 1983 and 31 March 2017. Based on the key questions, articles were retrieved and data extracted in parallel with comparison of results and discussion to resolve discrepancies. Variables assessed included study design and outcomes.ResultsA narrative synthesis was created for each question to describe the occurrence of, and clinical significance of, additional diagnostic findings from subsequent testing performed after CMA.ConclusionThese findings may be used to assist the laboratory and clinician when making recommendations about additional testing after CMA, as it impacts clinical care, counseling, and diagnosis.
| S-EPMC6410698 | biostudies-literature
Project description:PurposeCopy-number analysis to detect disease-causing losses and gains across the genome is recommended for the evaluation of individuals with neurodevelopmental disorders and/or multiple congenital anomalies, as well as for fetuses with ultrasound abnormalities. In the decade that this analysis has been in widespread clinical use, tremendous strides have been made in understanding the effects of copy-number variants (CNVs) in both affected individuals and the general population. However, continued broad implementation of array and next-generation sequencing-based technologies will expand the types of CNVs encountered in the clinical setting, as well as our understanding of their impact on human health.MethodsTo assist clinical laboratories in the classification and reporting of CNVs, irrespective of the technology used to identify them, the American College of Medical Genetics and Genomics has developed the following professional standards in collaboration with the National Institutes of Health (NIH)-funded Clinical Genome Resource (ClinGen) project.ResultsThis update introduces a quantitative, evidence-based scoring framework; encourages the implementation of the five-tier classification system widely used in sequence variant classification; and recommends "uncoupling" the evidence-based classification of a variant from its potential implications for a particular individual.ConclusionThese professional standards will guide the evaluation of constitutional CNVs and encourage consistency and transparency across clinical laboratories.
| S-EPMC7313390 | biostudies-literature
Project description:In the last few years, next-generation sequencing has led to enormous progress in deciphering monogenic forms of intellectual disability. Autosomal dominant intellectual disability (ADID) and X chromosomal intellectual disability (XLID) have been the focus of research. Apart from metabolic disorders, autosomal recessive intellectual disability (ARID) is still behind, probably because it is more heterogeneous and less prevalent in industrial populations. The prevalence of ARID in a cohort of affected children of an outbred population is estimated to be about 10%, with an upward tendency in still unclarified cases. The risk for ARID in children of first cousins or closer is a magnitude higher than for children of unrelated parents. Taken together, it seems that children of related parents are at a 2 to 3 times higher risk for ID. There are no prevalent ARID genes, pathways, or protein complexes and the functions of the affected proteins are very diverse and limited not only to neurological aspects. Thus, in a regular case, there is no reasoning for picking a few genes for a first diagnostic step, and a genetic diagnosis of ID in general, and ARID specifically, is better made using large panels or exome sequencing. In addition, in the last few months, evidence has been growing that many ARID genes are pleiotropic and that the resulting phenotypes may have a broad spectrum. For an exhaustive deciphering of the genetics of ARID, we suggest research at the level of single genes rather than large meta-analyses.
| S-EPMC6223757 | biostudies-literature
Project description:[This corrects the article DOI: 10.1371/journal.pone.0167562.].
| S-EPMC5344493 | biostudies-literature
Project description:We studied a case with suspected PIK3CD deficiency with a homozygous mutation in the patient in PIK3CD (c.1340-1 G>A). All other family members were tested and defined as carriers of the same mutation and are clinically healthy. The literature states that there is an AD but also an AR form of the disease (Immunodeficiency 14 A and B, respectively) linked to the gene. The clinical phenotype of the patient fits very well the description as LOF she suffers from severe, recurrent infections since infancy and has low overall IgG levels.
2023-12-31 | GSE216493 | GEO
Project description:Primary microcephaly (MCPH) is an autosomal recessive sporadic neurodevelopmental ailment with a trivial head size characteristic that is below 3-4 standard deviations. MCPH is the smaller upshot of an architecturally normal brain; a significant decrease in size is seen in the cerebral cortex. At birth MCPH presents with non-progressive mental retardation, while secondary microcephaly (onset after birth) presents with and without other syndromic features. MCPH is a neurogenic mitotic syndrome nevertheless pretentious patients demonstrate normal neuronal migration, neuronal apoptosis and neural function. Eighteen MCPH loci (MCPH1-MCPH18) have been mapped to date from various populations around the world and contain the following genes: Microcephalin, WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1, CDK6, CENPE, SASS6, MFSD2A, ANKLE2, CIT and WDFY3, clarifying our understanding about the molecular basis of microcephaly genetic disorder. It has previously been reported that phenotype disease is caused by MCB gene mutations and the causes of this phenotype are disarrangement of positions and organization of chromosomes during the cell cycle as a result of mutated DNA, centriole duplication, neurogenesis, neuronal migration, microtubule dynamics, transcriptional control and the cell cycle checkpoint having some invisible centrosomal process that can manage the number of neurons that are produced by neuronal precursor cells. Furthermore, researchers inform us about the clinical management of families that are suffering from MCPH. Establishment of both molecular understanding and genetic advocating may help to decrease the rate of this ailment. This current review study examines newly identified genes along with previously identified genes involved in autosomal recessive MCPH.
| S-EPMC6865151 | biostudies-literature
Project description:NHLBI TOPMed: African American Sarcoidosis Genetics Resource
| PRJNA342062 | ENA
Project description:A minority of patients with nonsyndromic autosomal recessive congenital ichthyosis (ARCI) display mutations in NIPAL4 (ICHTHYIN). This protein plays a role in epidermal lipid metabolism, although the mechanism is unknown. The study describes a moderate form of ARCI in an extended pedigree of American Bulldogs that is linked to the gene encoding ichthyin. The gross phenotype was manifest as a disheveled pelage shortly after birth, generalized scaling, and adherent brown scale with erythema of the abdominal skin. Pedigree analysis indicated an autosomal recessive mode of inheritance. Ultrastructurally, the epidermis showed discontinuous lipid bilayers, unprocessed lipid within corneocytes, and abnormal lamellar bodies. Linkage analysis, performed by choosing simple sequence repeat markers and single-nucleotide polymorphisms near genes known to cause ACRI, revealed an association with NIPAL4. NIPAL4 was identified and sequenced using standard methods. No mutation was identified within the gene, but affected dogs had a SINE element 5' upstream of exon 1 in a highly conserved region. Of 545 DNA samples from American Bulldogs, 32 dogs (17 females, 15 males) were homozygous for the polymerase chain reaction fragment. All affected dogs were homozygous, with parents heterozygous for the insertion. Immunolabeling revealed an absence of ichthyin in the epidermis. This is the first description of ARCI associated with decreased expression of NIPAL4 in nonhuman species.
| S-EPMC4492690 | biostudies-literature
Project description:BackgroundThe hypothesis of the Dilated Cardiomyopathy Precision Medicine Study is that most dilated cardiomyopathy has a genetic basis. The study returns results to probands and, when indicated, to relatives. While both the American College of Medical Genetics and Genomics/Association for Molecular Pathology and ClinGen's MYH7-cardiomyopathy specifications provide relevant guidance for variant interpretation, further gene- and disease-specific considerations were required for dilated cardiomyopathy. To this end, we tailored the ClinGen MYH7-cardiomyopathy variant interpretation framework; the specifications implemented for the study are presented here.MethodsModifications were created and approved by an external Variant Adjudication Oversight Committee. After a pilot using 81 probands, further adjustments were made, resulting in 27 criteria (9 modifications of the ClinGen MYH7 framework and reintroduction of 2 American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria that were deemed not applicable by the ClinGen MYH7 working group).ResultsThese criteria were applied to 2059 variants in a test set of 97 probands. Variants were classified as benign (n=1702), likely benign (n=33), uncertain significance (n=71), likely pathogenic (likely pathogenic; n=12), and pathogenic (P; n=3). Only 2/15 likely pathogenic/P variants were identified in Non-Hispanic African ancestry probands.ConclusionsWe tailored the ClinGen MYH7 criteria for our study. Our preliminary data show that 15/97 (15.5%) probands have likely pathogenic/P variants, most of which were identified in probands of Non-Hispanic European ancestry. We anticipate continued evolution of our approach, one that will be informed by new insights on variant interpretation and a greater understanding of the genetic architecture of dilated cardiomyopathy.Clinical trial registrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT03037632.
| S-EPMC8070981 | biostudies-literature