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ABSTRACT Functional annotation and interpretation of genetic variants are a critical step in genetic diagnosis, as it may lead to personalized therapeutic options and genetic counseling. While the number of confirmed pathogenic genetic variants in an individual is relatively low, the number of variants of uncertain significance (VOUS) can be considerably higher, increasing the number of potential carriers of genetic disorders. Thus, reducing uncertainty and assessing the real effect of VOUS are crucial for clinical and medical genetics. In this study, we evaluated the efficacy of genetic screening technologies in accurately predicting pathogenic variants and their corresponding disease prevalence in a cohort of over 6000 healthy individuals involved in assisted reproduction programs. Using data from 305 genes associated with recessive disorders, we determined the frequency of carriers of pathogenic variants and VOUS in our dataset and compared the predicted prevalence based on this information with reported population prevalence data. The higher predicted prevalence in some disorders when considering VOUS suggests a mostly benign effect. [ABSTRACT FROM AUTHOR]

Background: Skeletal dysplasia encompasses a heterogeneous group of genetic disorders characterized by an abnormal development of bones, joints, and cartilage. Two Chianina half‐sibling calves from consanguineous mating with congenital skeletal malformations and cardiac abnormalities were identified. Hypothesis/Objectives: To characterize the disease phenotype, to evaluate its genetic cause, and to determine the prevalence of the deleterious alleles in the Chianina population. Animals: Two affected calves, their parents and 332 Chianina bulls. Methods: The affected animals underwent clinicopathological investigation. Whole‐genome sequencing trio‐approach and PCR‐based assessment of the frequency of TDP‐glucose 4,6‐dehydratase (TGDS) and laminin subunit alpha 4 (LAMA4) alleles were performed. Results: The cases presented with retarded growth, poor nutritional status associated with muscular atrophy and angular deformities of the hindlimbs. Radiologic examination identified generalized osteopenia and shortening of the limb long bones. Necropsy showed osteochondrodysplastic limbs and dilatation of the heart right ventricle. On histological examination, the physeal cartilages were characterized by multifocal mild to moderate loss of the normal columnar arrangement of chondrocytes. Osteopenia also was observed. Genetic analysis identified a missense variant in TGDS and a splice‐site variant in LAMA4, both of which were homozygous in the 2 cases. Parents were heterozygous and allele frequency in the Chianina population for the TGDS variant was 5% and for the LAMA4 variant was 2%. Conclusions and Clinical Importance: Genetic findings identified 2 potentially pathogenic alleles in TGDS and LAMA4, but no clear mode of inheritance could be determined. [ABSTRACT FROM AUTHOR]

Abstract Background Skeletal dysplasia encompasses a heterogeneous group of genetic disorders characterized by an abnormal development of bones, joints, and cartilage. Two Chianina half‐sibling calves from consanguineous mating with congenital skeletal malformations and cardiac abnormalities were identified. Hypothesis/Objectives To characterize the disease phenotype, to evaluate its genetic cause, and to determine the prevalence of the deleterious alleles in the Chianina population. Animals Two affected calves, their parents and 332 Chianina bulls. Methods The affected animals underwent clinicopathological investigation. Whole‐genome sequencing trio‐approach and PCR‐based assessment of the frequency of TDP‐glucose 4,6‐dehydratase (TGDS) and laminin subunit alpha 4 (LAMA4) alleles were performed. Results The cases presented with retarded growth, poor nutritional status associated with muscular atrophy and angular deformities of the hindlimbs. Radiologic examination identified generalized osteopenia and shortening of the limb long bones. Necropsy showed osteochondrodysplastic limbs and dilatation of the heart right ventricle. On histological examination, the physeal cartilages were characterized by multifocal mild to moderate loss of the normal columnar arrangement of chondrocytes. Osteopenia also was observed. Genetic analysis identified a missense variant in TGDS and a splice‐site variant in LAMA4, both of which were homozygous in the 2 cases. Parents were heterozygous and allele frequency in the Chianina population for the TGDS variant was 5% and for the LAMA4 variant was 2%. Conclusions and Clinical Importance Genetic findings identified 2 potentially pathogenic alleles in TGDS and LAMA4, but no clear mode of inheritance could be determined.

Objectives: The purpose of the study is to identify the recessive diseases currently affecting real‐world pediatric patients in Taiwan, and whether current extended carrier screening panels have the coverage and detective power to identify the pathogenic variants in the carrier parents. Methods: A total of 132 trio‐samples were collected from May 2017 to March 2022. The participants were parents of pediatric intensive care unit patients who were critically ill or infants with abnormal newborn screening results. A retrospective carrier screening scheme was applied to analyze only the carrier status of pathogenic or likely pathogenic recessive variants resulting in diseases in their children. The recessive disorders diagnosed in our cohort were compared with the gene content in commercial panels. Results: Mutations in COQ4, PEX1, OTC, and IKBKG were the most frequently identified. In the parents of 44 children with confirmed diagnoses of recessive diseases, 47 (53.40%) screened positive for being the carriers of the same recessive disorders diagnosed in their children. The commercial panels covered 35.13% to 54.05% of the disorders diagnosed in this cohort. Conclusion: Clinicians and genetic counselors should be aware of the limitations of current extended carrier screening and interpret negative screening results with caution. Future panels should also consider genes with ethnically unique mutations such as pathogenic variants of the COQ4 gene in the East Asian population. Synopsis: The design of carrier screening panels still needs to take into consideration ethnic uniqueness or founder mutations in the targeted population. [ABSTRACT FROM AUTHOR]

Background: Orofacial anomalies occur due to incomplete fusion of developmental lines in the head and neck region. Dental anomalies regarded as the most common orofacial anomalies either in isolated or syndromic forms arise due to genetic and environmental factors. Among genetic influences, consanguineous marriages are considered as a significant predisposition factor in the transmission of congenital defects and several autosomal recessive diseases from one generation to other with an increased risk of detrimental effects on offspring. Aim: The present study was aimed to evaluate the prevalence and significant association between consanguinity and isolated dental anomalies with that of nonconsanguineous parents among south-Indian population. Methodology: A total of 116 participants with and without dental anomalies in isolated form pertaining to tooth size, shape, altered morphology, number and eruption were selected followed by brief case history. Participants with a positive history of consanguinity were categorized as Group A while others were categorized under Group B. Results: Sixty-four out of 116 participants (55.17%) showed positive consanguinity (Group A) among which 18 females (56%) and 14 males (44%) presented with isolated dental anomalies. 12 females (66.6%) and 9 males (64.2%) in Group A showed significance with first cousin (P = 0.00204) whereas no significance was observed in other consanguinity type (P = 0.7287). Nonetheless, the overall frequency of isolated dental anomalies was slightly higher in Group A than Group B that was statistically significant (P = 0.0213). Conclusion: A positive correlation between dental anomalies among offspring of consanguineous marriages revealed such prevalence may be attributed to increased risk of recessive deleterious gene expression or defective allele carried to offspring. [ABSTRACT FROM AUTHOR]

A newly identified subtype of hereditary axonal motor neuropathy, characterized by early proximal limb involvement, has been discovered in a cohort of 34 individuals with biallelic variants in von Willebrand factor A domain-containing 1 ( VWA1 ). This study further delineates the disease characteristics in a cohort of 20 individuals diagnosed through genome or exome sequencing, incorporating neurophysiological, laboratory and imaging data, along with data from previously reported cases across three different studies. Newly reported clinical features include hypermobility/hyperlaxity, axial weakness, dysmorphic signs, asymmetric presentation, dystonic features and, notably, upper motor neuron signs. Foot drop, foot deformities and distal leg weakness followed by early proximal leg weakness are confirmed to be initial manifestations. Additionally, this study identified 11 novel VWA1 variants, reaffirming the 10 bp insertion-induced p.Gly25ArgfsTer74 as the most prevalent disease-causing allele, with a carrier frequency of ∼1 in 441 in the UK and Western European population. Importantly, VWA1-related pathology may mimic various neuromuscular conditions, advocating for its inclusion in diverse gene panels spanning hereditary neuropathies to muscular dystrophies. The study highlights the potential of lower quality control filters in exome analysis to enhance diagnostic yield of VWA1 disease that may account for up to 1% of unexplained hereditary neuropathies., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Despite recent advancements in our understanding of genetic etiology and its molecular and physiological consequences, it is not yet clear what genetic features determine the inheritance pattern of a disease. To address this issue, we conducted whole exome sequencing analysis to characterize genetic variants in 1,180 Korean patients with neurological symptoms. The diagnostic yield for definitive pathogenic variant findings was 50.8%, after including 33 cases (5.9%) additionally diagnosed by reanalysis. Of diagnosed patients, 33.4% carried inherited variants. At the genetic level, autosomal recessive-inherited genes were characterized by enrichments in metabolic process, muscle organization and metal ion homeostasis pathways. Transcriptome and interactome profiling analyses revealed less brain-centered expression and fewer protein-protein interactions for recessive genes. The majority of autosomal recessive genes were more tolerant of variation, and functional prediction scores of recessively-inherited variants tended to be lower than those of dominantly-inherited variants. Additionally, we were able to predict the rates of carriers for recessive variants. Our results showed that genes responsible for neurodevelopmental disorders harbor different molecular mechanisms and expression patterns according to their inheritance patterns. Also, calculated frequency rates for recessive variants could be utilized to pre-screen rare neurodevelopmental disorder carriers. [ABSTRACT FROM AUTHOR]

In the last two decades, the molecular cause of six monogenic autosomal recessive disorders has been identified in native Italian beef cattle: two different ATP2A1 variants for the pseudomyotonia congenita, the first in Chianina and Romagnola (PMT1) and the second in Romagnola (PMT2); a KDM2B variant for the paunch calf syndrome (PCS) in Marchigiana and Romagnola; a NID1 variant for the congenital cataract (CC) in Romagnola; a LAMB1 variant for the hemifacial microsomia (HFM) in Romagnola; an ABCA12 variant for the ichthyosis fetalis (IF) in Chianina and a FA2H variant for the ichthyosis congenita (IC) in Chianina. The aim of this study was to evaluate the potential impact of these disorders in the affected Italian populations. For this purpose, 3331 Chianina, 2812 Marchigiana and 1680 Romagnola bulls born in the last 40 years were considered. The allelic frequency (AF) of the variant for PMT1 was 1.0% in Romagnola, 4.6% in Marchigiana and 5.9% in Chianina. The AF of the variant for PMT2 was 3.3% in Romagnola and 0% in the other two breeds. The AF of the variant for PCS was 11.7% in Romagnola, 2.0% in Marchigiana and 0% in Chianina. The AF of the variants for CC, HFM, IF and IC resulted below 3%, being the variants detected only in the breed populations in which they were previously reported. Considering a selected male population in the single breed, Chianina showed carrier prevalence of 11.9% for PMT1, 7.7% for IC and 6.4% for IF. Romagnola showed carrier prevalence of 23.4% for PCS, 6.7% for PMT2, 4.1% for HFM, 3.2% for CC and 2.0% for PMT1. Marchigiana showed carrier prevalence of 9.1% for PMT1 and 4.0% for PCS. With respect to the Romagnola cattle, the concerning presence of a total of five defect alleles in the population hampers a general approach based on the prevention of carriers from artificial insemination. However, identification of carriers may allow conscious mating to prevent the risk of homozygous descendants as well as the spread of heterozygous offspring. Therefore, systematic genotyping for all seven known harmful alleles is recommended to prevent risk mating between carriers, in particular to avoid the occurrence of affected offspring.

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Purpose: Identifying pathogenic noncoding variants is challenging. A single protein-altering variant is often identified in a recessive gene in individuals with developmental disorders (DD), but the prevalence of pathogenic noncoding "second hits" in trans with these is unknown., Methods: In 4073 genetically undiagnosed rare-disease trio probands from the 100,000 Genomes project, we identified rare heterozygous protein-altering variants in recessive DD-associated genes. We identified rare noncoding variants on the other haplotype in introns, untranslated regions, promoters, and candidate enhancer regions. We clinically evaluated the top candidates for phenotypic fit and performed functional testing where possible., Results: We identified 3761 rare heterozygous loss-of-function or ClinVar pathogenic variants in recessive DD-associated genes in 2430 probands. For 1366 (36.3%) of these, we identified at least 1 rare noncoding variant in trans. Bioinformatic filtering and clinical review, revealed 7 to be a good clinical fit. After detailed characterization, we identified likely diagnoses for 3 probands (in GAA, NPHP3, and PKHD1) and candidate diagnoses in a further 3 (PAH, LAMA2, and IGHMBP2)., Conclusion: We developed a systematic approach to uncover new diagnoses involving compound heterozygous coding/noncoding variants and conclude that this mechanism is likely to be a rare cause of DDs., Competing Interests: Conflict of Interest Elena Arciero is a current employee of Flagship Labs 86, Flagship Pioneering. Nicola Whiffin receives research funding from Novo Nordisk and has consulted for Argobio. All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The effects of 2 deleterious recessive haplotypes on reproduction performance of Ayrshire cattle, Ayrshire Haplotype 1 (AH1) and Ayrshire Haplotype 2 (AH2), were investigated in Canadian Ayrshire cattle. We calculated their phenotypic effects on stillbirth (SB) rate and 56-d nonreturn rate (NRR) by estimating the interaction of service sire carrier status with maternal grandsire carrier status using the official Canadian evaluation models for those 2 traits. The interaction term included 9 subclasses for the 3 possible statuses of each bull: haplotype carrier, noncarrier, or not genotyped. For AH1, 394 carriers and 1,433 noncarriers were available, whereas 313 carriers and 1,543 noncarriers were available for the AH2 haplotype. The number of matings considered for SB was 34,312 for heifers (first parity) and 115,935 for cows (later parities). For NRR, 49,479 matings for heifers and 160,528 for cows were used to estimate the haplotype effects. We observed a negative effect of AH1 on SB rates, which was 2.0% higher for matings of AH1-carrier sires to dams that had an AH1-carrier sire; this effect was found for both heifers and cows. However, AH1 had small, generally nonsignificant effects on NRR. The AH2 haplotype had a substantial negative effect on NRR, with 5.1% more heifers and 4.0% more cows returning to service, but the effects on SB rates were inconsistent and mostly small effects. Our results validate the harmful effects of AH1 and AH2 on reproduction traits in the Canadian Ayrshire population. This information will be of great interest for the dairy industry, allowing producers to make mating decisions that would reduce reproductive losses. [ABSTRACT FROM AUTHOR]

Disclosure of affected breed without disclosure of major progenitors has been the usual practice in scientific papers reporting recessive heritable disorders of cattle. Before molecular genetics, carrier identity could not be used by breeders to control causal mutations because phenotypically normal heterozygotes among genetically related animals could not be detected other than by test mating. Accurate, low-cost DNA tests fundamentally changed this situation. Genomics can provide relief from the old problem of emerging recessive disorders in cattle breeding, but greater transparency of genotype data between breeders is necessary to fully exploit the opportunities for cost-efficient genetic disease control. Effective control of several recessive disorders has been demonstrated in Angus cattle, based entirely on voluntary DNA testing by breeders but mandatory public disclosure of test results and genotype probabilities for all registered animals. When a DNA test is available, major progenitors (particularly bulls from which semen has been distributed) should be identified and disclosed concurrently with the affected breed. As a minimum, whenever possible the closest common ancestors in the pedigrees of the parents of homozygous mutants should be disclosed after confirmation of carrier status. Progenitor disclosure in scientific publications should occur in cooperation with breed societies, which should have the opportunity to advise breeders and initiate management programs before scientific publication. Unless properly managed, genomic enhancement of animal selection using SNP markers may increase inbreeding, co-ancestry and emergence of recessive disorders. The information systems and genotype disclosure policies of some breed societies will be increasingly challenged, particularly with accelerating mutation discovery using next-generation sequencing. [ABSTRACT FROM AUTHOR]

Phenotypes from the August 2015 US national genetic evaluation were used to compute phenotypic effects of 18 recessive haplotypes in Ayrshire (n = 1), Brown Swiss (n = 5), Holstein (n = 10), and Jersey (n = 2) cattle on milk, fat, and protein yields, somatic cell score (SCS), single-trait productive life (PL), daughter pregnancy rate (DPR), heifer conception rate (HCR), and cow conception rate (CCR). The haplotypes evaluated were Ayrshire haplotype 1, Brown Swiss haplotypes 1 and 2, spinal dysmyelination, spinal muscular atrophy, Weaver Syndrome, brachyspina, Holstein cholesterol deficiency, Holstein haplotypes 1 to 5, bovine leukocyte adhesion deficiency, complex vertebral malformation, mulefoot (syndactyly), and Jersey haplotypes 1 and 2. When causal variants are unknown and tests are based only on single nucleotide polymorphism haplotypes, it can sometimes be difficult to accurately determine carrier status. For example, 2 Holstein haplotypes for cholesterol deficiency have the same single nucleotide polymorphism genotype, but only one of them carries the causative mutation. Genotyped daughters of carrier bulls included in the analysis ranged from 8 for Weaver Syndrome to 17,869 for Holstein haplotype 3. Lactation records preadjusted for nongenetic factors and direct genomic values (DGV) were used to estimate phenotypic and genetic effects of recessive haplotypes, respectively. We found no phenotypic or genetic differences between carriers and noncarriers of Ayrshire or Brown Swiss defects. Several associations were noted for Holstein haplotypes, including fat and HCR for Holstein haplotype 0 carriers; milk, protein, SCS, PL, and fertility for Holstein haplotype 1; protein, PL, CCR, and HCR for Holstein haplotype 2; milk, protein, and fertility for Holstein haplotype 4; and protein yield and DPR for Holstein haplotype 5. There were no differences among bovine leukocyte adhesion deficiency carriers, but complex vertebral malformation affected fat yield and mulefoot carriers had higher SCS and lower PL DGV. Jersey haplotype 1 was not associated with any phenotypic effects, but we noted significant differences among DGV for fat, protein, PL, DPR, CCR, and HCR. Jersey haplotype 2 was associated only with lower phenotypic CCR. Effects of the recessive haplotypes on other traits studied generally were small even when significant. Almost $11 million of economic losses per year due to reduced fertility and perinatal calf death in the US population can be avoided by selecting mate pairs that will not produce affected embryos. Carrier animals may continue to be selected if the merit of their favorable alleles exceeds the loss from their recessive alleles, but carrier bulls can be generally avoided without reducing the average genetic merit of the sires available for mating. [ABSTRACT FROM AUTHOR]

Currently, there is no consensus regarding services required to help families with consanguineous marriages manage their increased genetic reproductive risk. Genetic services for communities with a preference for consanguineous marriage in the UK remain patchy, often poor. Receiving two disparate explanations of the cause of recessive disorders (cousin marriage and recessive inheritance) leads to confusion among families. Further, the realisation that couples in non-consanguineous relationships have affected children leads to mistrust of professional advice. British Pakistani families at-risk for recessive disorders lack an understanding of recessive disorders and their inheritance. Such an understanding is empowering and can be shared within the extended family to enable informed choice. In a three-site qualitative study of British Pakistanis, we explored family and health professional perspectives on recessively inherited conditions. Our findings suggest, firstly, that family networks hold strong potential for cascading genetic information, making the adoption of a family-centred approach an efficient strategy for this community. However, this is dependent on provision of high-quality and timely information from health care providers. Secondly, families' experience was of ill-coordinated and time-starved services, with few having access to specialist provision from Regional Genetics Services; these perspectives were consistent with health professionals' views of services. Thirdly, we confirm previous findings that genetic information is difficult to communicate and comprehend, further complicated by the need to communicate the relationship between cousin marriage and recessive disorders. A communication tool we developed and piloted is described and offered as a useful resource for communicating complex genetic information. [ABSTRACT FROM AUTHOR]

Carrier screening for certain diseases is recommended by major medical and Ashkenazi Jewish (AJ) societies. Most carrier screening panels test only for common, ethnic-specific variants. However, with formerly isolated ethnic groups becoming increasingly intermixed, this approach is becoming inadequate. Our objective was to develop a rigorous process to curate all variants, for relevant genes, into a database and then apply stringent clinical validity classification criteria to each in order to retain only those with clear evidence for pathogenicity. The resulting variant set, in conjunction with next-generation DNA sequencing (NGS), then affords the capability for an ethnically diverse, comprehensive, highly specific carrier-screening assay. The clinical utility of our approach was demonstrated by screening a pan-ethnic population of 22,864 individuals for Bloom syndrome carrier status using a BLM variant panel comprised of 50 pathogenic variants. In addition to carriers of the common AJ founder variant, we identified 57 carriers of other pathogenic BLM variants. All variants reported had previously been curated and their clinical validity documented, or were of a type that met our stringent, preassigned validity criteria. Thus, it was possible to confidently report an increased number of Bloom's syndrome carriers compared to traditional, ethnicity-based screening, while not reducing the specificity of the screening due to reporting variants of unknown clinical significance. [ABSTRACT FROM AUTHOR]

• Deleterious alleles contribute strongly to genetic load. • Inbreeding increases the probability of the occurrence of homozygous mutants. • Knowing the frequency of harmful alleles is important to take preventive measures. • The frequency of deleterious alleles in Italian beef cattle populations confirms the breeders' concern. • Systematic genotyping of sires is effective to prevent risk mating. In the last two decades, the molecular cause of six monogenic autosomal recessive disorders has been identified in native Italian beef cattle: two different ATP2A1 variants for the pseudomyotonia congenita, the first in Chianina and Romagnola (PMT1) and the second in Romagnola (PMT2); a KDM2B variant for the paunch calf syndrome (PCS) in Marchigiana and Romagnola; a NID1 variant for the congenital cataract (CC) in Romagnola; a LAMB1 variant for the hemifacial microsomia (HFM) in Romagnola; an ABCA12 variant for the ichthyosis fetalis (IF) in Chianina and a FA2H variant for the ichthyosis congenita (IC) in Chianina. The aim of this study was to evaluate the potential impact of these disorders in the affected Italian populations. For this purpose, 3331 Chianina, 2812 Marchigiana and 1680 Romagnola bulls born in the last 40 years were considered. The allelic frequency (AF) of the variant for PMT1 was 1.0% in Romagnola, 4.6% in Marchigiana and 5.9% in Chianina. The AF of the variant for PMT2 was 3.3% in Romagnola and 0% in the other two breeds. The AF of the variant for PCS was 11.7% in Romagnola, 2.0% in Marchigiana and 0% in Chianina. The AF of the variants for CC, HFM, IF and IC resulted below 3%, being the variants detected only in the breed populations in which they were previously reported. Considering a selected male population in the single breed, Chianina showed carrier prevalence of 11.9% for PMT1, 7.7% for IC and 6.4% for IF. Romagnola showed carrier prevalence of 23.4% for PCS, 6.7% for PMT2, 4.1% for HFM, 3.2% for CC and 2.0% for PMT1. Marchigiana showed carrier prevalence of 9.1% for PMT1 and 4.0% for PCS. With respect to the Romagnola cattle, the concerning presence of a total of five defect alleles in the population hampers a general approach based on the prevention of carriers from artificial insemination. However, identification of carriers may allow conscious mating to prevent the risk of homozygous descendants as well as the spread of heterozygous offspring. Therefore, systematic genotyping for all seven known harmful alleles is recommended to prevent risk mating between carriers, in particular to avoid the occurrence of affected offspring. [ABSTRACT FROM AUTHOR]

Whole exome sequencing ( WES) has greatly facilitated the identification of causal mutations for diverse human genetic disorders. We applied WES as a molecular diagnostic tool to identify disease-causing genes in consanguineous families in Qatar. Seventeen consanguineous families with diverse disorders were recruited. Initial mutation screening of known genes related to the clinical diagnoses did not reveal the causative mutations. Using WES approach, we identified the definitive disease-causing mutations in four families: (i) a novel nonsense homozygous (c. 1034C>G) in PHKG2 causing glycogen storage disease type 9C ( GSD9C) in a male with initial diagnosis of GSD3; (ii) a novel homozygous 1-bp deletion (c.915del) in NSUN2 in a male proband with Noonan-like syndrome; (iii) a homozygous SNV (c. 1598C>G) in exon 11 of IDUA causing Hurler syndrome in a female proband with unknown clinical diagnosis; (iv) a de novo known splicing mutation (c.1645+ 1G>A) in PHEX in a female proband with initial diagnosis of autosomal recessive hypophosphatemic rickets. Applying WES as a diagnostic tool led to the unambiguous identification of disease-causing mutations in phenotypically complex disorders or correction of the initial clinical diagnosis in ˜25% of our cases. [ABSTRACT FROM AUTHOR]

Despite recent advancements in our understanding of genetic etiology and its molecular and physiological consequences, it is not yet clear what genetic features determine the inheritance pattern of a disease. To address this issue, we conducted whole exome sequencing analysis to characterize genetic variants in 1,180 Korean patients with neurological symptoms. The diagnostic yield for definitive pathogenic variant findings was 50.8%, after including 33 cases (5.9%) additionally diagnosed by reanalysis. Of diagnosed patients, 33.4% carried inherited variants. At the genetic level, autosomal recessive-inherited genes were characterized by enrichments in metabolic process, muscle organization and metal ion homeostasis pathways. Transcriptome and interactome profiling analyses revealed less brain-centered expression and fewer protein-protein interactions for recessive genes. The majority of autosomal recessive genes were more tolerant of variation, and functional prediction scores of recessively-inherited variants tended to be lower than those of dominantly-inherited variants. Additionally, we were able to predict the rates of carriers for recessive variants. Our results showed that genes responsible for neurodevelopmental disorders harbor different molecular mechanisms and expression patterns according to their inheritance patterns. Also, calculated frequency rates for recessive variants could be utilized to pre-screen rare neurodevelopmental disorder carriers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, (Copyright © 2022 Park, Jang, Lee, Kim, Sim, Jeon, Hong, Lee, Lee, Jeon, Lee, Lee, Kim, Kim, Yoon, Lim, Kim, Kim, Ko, Cho, Lee, Choi and Chae.)

The article presents an update on "One Founder/One Gene Hypothesis in a New Expanding Population," by Evelyne Heyer, published in 1999. The paper aims to understand how inherited recessive disorders became prevalent in the Saguenay region of Quebec. It also intends to discover if a single founder introduced each disorder to its ancestral population. With the use of ascending genealogies, the increase in carrier frequency represents a genetic drift that confirms the hypothesis.

Copyright of Monatsschrift Kinderheilkunde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Demands for expanded carrier screening (ECS) are growing and ECS is becoming an important part of obstetrics practice and reproductive planning. The aim of this study is to evaluate the feasibility of a small-size ECS panel in clinical implementation and investigate Chinese couples' attitudes towards ECS. An ECS panel containing 11 recessive conditions was offered to Chinese pregnant women below 16 gestational weeks. Sequential testing of their partners was recommended for women with a positive carrier status. The reproductive decision and pregnancy outcome were surveyed for at-risk couples. A total of 1321 women performed ECS successfully and the overall carrier rate was 19.23%. The estimated at-risk couple rate was 0.83%. Sequential testing was performed in less than half of male partners. Eight at-risk couples were identified and four of them performed prenatal diagnosis. Our study demonstrated that a small-size ECS panel could yield comparable clinical value to a larger-size panel when the carrier rate of the individual condition is equal or greater than 1%. In addition, more than half of male partners whose wives were carriers declined any types of sequential testing possibly due to a lack of awareness and knowledge of genetic disorders. Genetic education is warranted for the better implementation of ECS. [ABSTRACT FROM AUTHOR]

This abstract describes the establishment of a new DNA biobank to support the discovery of new recessive genetic disorders in the U.S. dairy cattle population. High-density single-nucleotide polymorphism genotypes have recently been used to identify a number of novel recessive mutations that adversely affect fertility in dairy cattle, but the lack of consistent procedures for collecting DNA samples and supporting information for those projects underscores the need for a standardized process. The new Dairy Calf DNA BioBank in Beltsville, MD, is a repository for the collection and storage of samples. It complements the automated process of searching for new haplotypes that is part of the national dairy genetic evaluation system. The goal is to collect whole blood from calves that are born dead or that die shortly after birth, particularly if the calf appears to suffer from a congenital defect, as well as DNA from its dam and a sibling in the herd. Kits that include all sampling materials, a pre-paid return shipping label, a material transfer agreement, and a protocol for sample collection are shipped upon receipt of a request through the website. DNA providers are also able to provide substantial descriptive information about the calves for which they're providing blood, including digital photographs. When the samples are received in Beltsville, the DNA is extracted and stored for future analysis. The material transfer agreement ensures that a clear chain of permissions is available for every sample. If a pattern emerges to suggest that there is a new recessive genetic disorder in the population, the DNA is available for sequencing and causal variant discovery. Standardized protocols for DNA extraction and whole-genome sequencing will help ensure that data are of high quality. Information on carrier status for new recessives will be distributed through the Council on Dairy Cattle Breeding (Bowie, MD). The URL for the BioBank website is: http://aipl.arsusda.gov/BioBank/. [ABSTRACT FROM AUTHOR]

Objective: To explore attitudes of clinical and molecular geneticists about the implementation of multi-disease or expanded carrier screening (ECS) for monogenic recessive disorders., Design: Qualitative; semistructured interviews., Setting: In person or via Skype. Interviews were audiorecorded and transcribed verbatim., Participants: European clinical and molecular geneticists with expertise in carrier screening (N = 16)., Methods: Inductive content analysis was used to identify common content categories in the data., Results: Participants recognized important benefits of ECS, but they also identified major challenges, including limited benefit of ECS for most couples in the general population, lack of knowledge on carrier screening among nongenetic health care providers and the general public, potential negative implications of ECS for society, and limited economic resources. Participants favored an evidence-based approach to the implementation of population-wide ECS and were reluctant to actively offer ECS in the absence of demonstrable benefits. However, there was a consensus among the participants that ECS should be made available to couples who request the test. In addition, they believed ECS could be routinely offered to all people who use assisted reproduction., Conclusion: Although a limited ECS offer is practical, it also raises concerns over equality in access to screening. A comprehensive risk-benefit analysis is needed to determine the desirability of systematic population-wide ECS., (Copyright © 2017 AWHONN, the Association of Women’s Health, Obstetric and Neonatal Nurses. Published by Elsevier Inc. All rights reserved.)