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Roifman syndrome is a rare autosomal recessive inherited syndromic immunodeficiency. We wish to add to the available literature by reporting two brothers with clinical, radiological and immunological features of Roifman syndrome, confirmed on whole exome sequencing. We report an excellent response to subcutaneous immunoglobulin therapy in both brothers, reducing infection burden and hospital admissions. New radiological features are also described here which may assist in the diagnosis of other patients.

A woman in her 30s was referred to our neurology outpatient clinic following an incidental finding of significant bilateral and symmetric basal ganglia, thalamic, cerebellar and subcortical white matter calcification on brain CT and MRI. A diagnosis of asymptomatic primary familial brain calcification (PFBC) was made. Targeted genetic testing revealed a likely pathogenic variant in the

International audience; Genomic epidemiology has guided research and policy for various viral pathogens and there has been a parallel effort towards using genomic epidemiology to combat diseases that are caused by eukaryotic pathogens, such as the malaria parasite. However, the central concept of viral genomic epidemiology, namely that of measurably mutating pathogens, does not apply easily to sexually recombining parasites. Here we introduce the related but different concept of measurably recombining malaria parasites to promote convergence around a unifying theoretical framework for malaria genomic epidemiology. Akin to viral phylodynamics, we anticipate that an inferential framework developed around recombination will help guide practical research and thus realize the full public health potential of genomic epidemiology for malaria parasites and other sexually recombining pathogens.

VPS13D is a recently described gene. Worldwide, only 15 families with 23 affected individuals have been reported with a VPS13D-based disease. Mutated VPS13D causes a complex phenotype with a hyperkinetic movement disorder and ataxia, especially in childhood onset disease. The clinical phenotype of the rare adult-onset cases consists of cerebellar ataxia and/or spastic paraplegia. Here, we report the extensive clinical, laboratory and genetic findings of two offspring from consanguineous parents, with ages of disease onset at 57 and 49 with VPS13D-based ataxia. Although conventional magnetic resonance imaging showed mild cerebellar and cerebral atrophy, diffusion tensor imaging, applied for the first time for VPS13D patients, revealed prominent atrophy in U fibers and cerebellopontine tracts. Whole exome sequencing analysis revealed a biallelic Ala4210Val mutation in the VPS13D, reported only once in the literature. Complementary screening of our in-house database consisting of 295 ataxia and hereditary spastic paraplegia patients revealed two further ataxia patients with novel VPS13D variants. Screening the control cohort for VPS13D variants revealed one asymptomatic individual carrying a novel VPS13D variant. In this study, the phenotypic spectrum of VPS13D-based disease is expanded with the description of pre-senile onset predominant ataxia. Further, with the additional novel mutations described, the report is expected to contribute to the understanding of the yet elusive phenotype-genotype correlations in the rare VPS13D-based movement disorder.

Digenic Alport syndrome refers to the inheritance of pathogenic variants in COL4A5 plus COL4A3 or COL4A4 or in COL4A3 plus COL4A4. Where digenic Alport syndrome includes a pathogenic COL4A5 variant, the consequences depend on the sex of the affected individual, COL4A5 variant ?severity,? and the nature of the COL4A3 or COL4A4 change. A man with a pathogenic COL4A5 variant has all his collagen IV ?3?4?5-heterotrimers affected, and an additional COL4A3 or COL4A4 variant may not worsen disease. A woman with a pathogenic COL4A5 variant has on average 50% of her heterotrimers affected, which is increased to 75% with a further COL4A3 or COL4A4 variant and associated with a higher risk of proteinuria. In digenic Alport syndrome with pathogenic COL4A3 and COL4A4 variants, 75% of the heterotrimers are affected. The COL4A3 and COL4A4 genes occur head-to-head on chromosome 2, and inheritance is autosomal dominant when both variants affect the same chromosome (in cis) or recessive when they affect different chromosomes (in trans). This form of digenic disease results in increased proteinuria and a median age of kidney failure intermediate between autosomal dominant and autosomal recessive Alport syndrome. Previous guidelines have suggested that all pathogenic or likely pathogenic digenic variants should be identified and reported. Affected family members should be identified, treated, and discouraged from kidney donation. Inheritance within a family is easier to predict if the two variants are considered independently and if COL4A3 and COL4A4 variants are known to be inherited on the same or different chromosomes.

Very few studies have shown the real origin and timing of de novo variants (DNV) implicated in von Willebrand disease (VWD). We investigated four families with type 2 VWD. First, we conducted linkage analysis using single nucleotide variant genotyping to recognize the possible provenance of DNV. Second, we performed amplification refractory mutation system-quantitative polymerase chain reaction to confirm the real origin of variant (~0% mutant cells) or presence of a genetic mosaic variant (0%-50% mutant cells) in three embryonic germ layer-derived tissues and sperm cells. Then, three possible timings of DNV were categorized based on the relative likelihood of occurrence according to the number of cell divisions during embryogenesis. Two each with type 2B VWD (proband 1 p.Arg1308Cys, proband 4 p.Arg1306Trp) and type 2A VWD (proband 2 p.Leu1276Arg, proband 3 p.Ser1506Leu) were identified. Variant origins were identified for families 1, 2 and 3 and confirmed to originate from the mother, father and father, respectively. However, the father of family 4 was confirmed to have isolated germline mosaicism with 2.2% mutant sperm cells. Further investigation confirmed the paternal grandfather to be the origin of variant. Thus, we proposed that DNV originating from the two fathers most likely occurred at the single sperm cell, the one originating from the mother occurred at the zygote during the first few cellular divisions; alternatively, in family 4, the DNV most likely occurred at the early postzygotic development in the father. Our findings are essential for understanding genetic pathogenesis and providing accurate genetic counselling.

By providing additional opportunities for coalescence within families, the presence of consanguineous unions in a population reduces coalescence times relative to non-consanguineous populations. First-cousin consanguinity can take one of six forms differing in the configuration of sexes in the pedigree of the male and female cousins who join in a consanguineous union: patrilateral parallel, patrilateral cross, matrilateral parallel, matrilateral cross, bilateral parallel, and bilateral cross. Considering populations with each of the six types of first-cousin consanguinity individually and a population with a mixture of the four unilateral types, we examine coalescent models of consanguinity. We previously computed, for first-cousin consanguinity models, the mean coalescence time for X-chromosomal loci and the limiting distribution of coalescence times for autosomal loci. Here, we use the separation-of-time-scales approach to obtain the limiting distribution of coalescence times for X-chromosomal loci. This limiting distribution has an instantaneous coalescence probability that depends on the probability that a union is consanguineous; lineages that do not coalesce instantaneously coalesce according to an exponential distribution. We study the effects on the coalescence time distribution of the type of first-cousin consanguinity, showing that patrilateral-parallel and patrilateral-cross consanguinity have no effect on X-chromosomal coalescence time distributions and that matrilateral-parallel consanguinity decreases coalescence times to a greater extent than does matrilateral-cross consanguinity.

PIGA (PIG class A) gene codes for the PIG-A protein, which is a catalytic subunit of GPI-GlcNAc transferase. GPI-anchored proteins play an important role in the metabolism of mammals. Somatic variants of PIGA genes in bone marrow hematopoietic stem cells often result in paroxysmal nocturnal haemoglobinuria, and the germline PIGA variants cause multiple congenital anomalies hypotonia seizures syndrome 2 (MCAHS2) because of glycosylphosphatidylinositol metabolic abnormalities.Whole exome sequencing was performed on peripheral blood sample of the patient with MCAHS2. A novel germline PIGA variant was found, and Sanger sequencing was performed as verification for the variant. After that, we used the keywords to retrieve relevant reports and provided a literature review.A novel hemizygous germline PIGA variant (NM_002641.3:c.971G A) at exon4 was identified through whole exome sequencing. And it was a highly probable pathogenic variant. Sanger sequencing yielded consistent results. The missense variant cause change of p.(Cys324Tyr) in the transcription product according to the predicted outcomes.We reported a case of MCAHS2 caused by a novel PIGA variant. Following a review of the literature, we suggested that MCAHS2 should be considered as a disorder spectrum consisting of core symptoms, multi-system impairment, and premature death. The core symptoms include hypotonia, psychomotor delay, epilepsy (intractable epilepsy mostly) and early death. Core symptoms nearly happened to almost all patients. Meanwhile, MCAHS2 involves a wide range of organ and system impairments with changeable form.

Unlike the autosomal dominant inheritance of neurofibromatosis 2, there are no known inherited risk factors for sporadic, unilateral vestibular schwannoma (VS), which comprise most VS cases. The authors tested a hypothesis positing a genetic contribution to predisposition to these lesions by analyzing familial clustering of cases.Familial clustering of individuals with unilateral VS was analyzed in two independent genealogical resources with linked diagnosis data: the Veterans Health Administration Genealogy Resource and the Utah Population Database. Tests for excess relatedness, estimation of relative risks (RRs) in close and distant relatives, and identification of pedigrees with a significant excess of unilateral VS among descendants were performed.The average pairwise relatedness of the Veterans Health Administration Genealogy Resource VS cases significantly exceeded the expected relatedness ( p = 0.016), even when close relationships were ignored ( p = 0.002). RR for third- and fifth-degree relatives developing VS were significantly elevated (RR, 60.83; p = 0.0005; 95% confidence interval [CI], 7.37-219.73) and (RR, 11.88; p = 0.013; 95% CI, 1.44-42.90), respectively. No VS-affected first-, second-, or fourth-degree relatives were observed. In the Utah Population Database population, no first- or second-degree relatives with VS were observed. RR for fifth-degree relatives developing VS was significantly elevated (RR, 2.23; p = 0.009; 95% CI, 1.15-3.90).These results provide strong evidence for an inherited predisposition to sporadic, unilateral VS. This study exhibits the value of genealogical resources with linked medical data for examining hypotheses regarding inherited predisposition. The high-risk unilateral VS pedigrees identified in two independent resources provide a powerful means of pursuing predisposition gene identification.

This focused revision builds on the expert opinions from the original publications of 'Recommendations for human standardized pedigree nomenclature' published in 1995 and updated in 2008. Our review of medical publications since 2008 did not identify any fundamental systematic alternative pedigree nomenclature. These findings attest to the relevance of most of the nomenclature with the critical exception of the nomenclature used to denote sex assigned at birth and gender. While we are not recommending the creation of any new pedigree symbols, a major focus of this publication is clarification of the use of symbols and language in the description of the distinction between sex and gender, with a view to ensuring safe and inclusive practice for people who are gender-diverse or transgender. In addition, we recommend modifications to the way that carrier status is depicted. Our goal is to respect individual differences and identities while maintaining biologically, clinically, and genetically meaningful information.

Low-frequency sensorineural hearing loss (SNHL) is a rare hearing impairment affecting frequencies below 1000 Hz, previously associated with DIAPH1, WSF1, MYO7A, TNC, SLC26A4 or CCDC50 genes. By exome sequencing, we report a novel nonsense variant in CENPP gene, segregating low-frequency SNHL in five affected members in a Swiss family with autosomal dominant inheritance pattern. Audiological evaluation showed up-sloping audiometric configuration with mild-to-moderate losses below 1000 Hz, that progresses to high-frequencies over time. Protein modeling shows that the variant truncates five amino acids at the end, losing electrostatic interactions that alter protein stability. CENPP gene is expressed in the supporting cells of the organ of Corti and takes part as a subunit of the Constitutive Centromere Associated Network in the kinetochore, that fixes the centromere to the spindle microtubules. We report CENPP as a new candidate gene for low-frequency SNHL. Further functional characterization might enable us to elucidate its molecular role in SNHL.

Item does not contain fulltext Biallelic loss-of-function variants in the TBC1D2B gene were recently reported as a cause of a neurodevelopmental disorder with seizures and gingival overgrowth. Here, we report two male siblings with the similar clinical characteristics. They started with gingival overgrowth and bilateral growth of soft tissues in the malar region at 3 years of age, which evolved with significant maxillary hypertrophy and compression of the brainstem due to fibrous dysplasia of facial bones. After disease evolution, they presented with mental deterioration, limb tremors, and gait ataxia. One of them also presented with seizures. Whole exome sequencing revealed a novel biallelic frameshift variant [c.595del; p.(Val199Trpfs*22)] in the TBC1D2B gene in both patients, which was confirmed and found in heterozygous state in each of their parents. There are strong similarities in clinical characteristics, age of onset, and evolution between the patients described here and cases reported in the literature, including cherubism-like phenotype with progressive gingival overgrowth and seizures. This is the fourth family in the world in which a biallelic loss-of-function variant in the TBC1D2B gene is associated with this phenotype. These results support that loss of TBC1D2B is the cause of this rare condition.

The genealogy process is typically the most time-consuming part of-and a limiting factor in the success of-forensic genetic genealogy, which is a new approach to solving violent crimes and identifying human remains. We formulate a stochastic dynamic program that-given the list of matches and their genetic distances to the unknown target-chooses the best decision at each point in time: which match to investigate (i.e., find its ancestors and look for most recent common ancestors between the match and the target), which set of potential most recent common ancestors to descend from (i.e., find its descendants, with the goal of identifying a marriage between the maternal and paternal sides of the target's family tree), or whether to terminate the investigation. The objective is to maximize the probability of finding the target minus a cost associated with the expected size of the final family tree. We estimate the parameters of our model using data from 17 cases (eight solved, nine unsolved) from the DNA Doe Project. We assess the Proposed Strategy using simulated versions of the 17 DNA Doe Project cases, and compare it to a Benchmark Strategy that ranks matches by their genetic distance to the target and only descends from known common ancestors between a pair of matches. The Proposed Strategy solves cases ≈10 - fold faster than the Benchmark Strategy, and does so by aggressively descending from a set of potential most recent common ancestors between the target and a match even when this set has a low probability of containing the correct most recent common ancestor. Our analysis provides a mathematical foundation for improving the genealogy process in forensic genetic genealogy.

Skeletal dysplasias comprise a large spectrum of mostly monogenic disorders affecting bone growth, patterning, and homeostasis, and ranging in severity from lethal to mild phenotypes. This study aimed to underpin the genetic cause of skeletal dysplasia in three unrelated families with variable skeletal manifestations. The six affected individuals from three families had severe short stature with extreme shortening of forelimbs, short long-bones, and metatarsals, and brachydactyly (family 1); mild short stature, platyspondyly, and metaphyseal irregularities (family 2); or a prenatally lethal skeletal dysplasia with kidney features suggestive of a ciliopathy (family 3). Genetic studies by whole genome, whole exome, and ciliome panel sequencing identified in all affected individuals biallelic missense variants in KIF24, which encodes a kinesin family member controlling ciliogenesis. In families 1 and 3, with the more severe phenotype, the affected subjects harbored homozygous variants (c.1457A>G; p.(Ile486Val) and c.1565A>G; p.(Asn522Ser), respectively) in the motor domain which plays a crucial role in KIF24 function. In family 2, compound heterozygous variants (c.1697C>T; p.(Ser566Phe)/c.1811C>T; p.(Thr604Met)) were found C-terminal to the motor domain, in agreement with a genotype-phenotype correlation. In vitro experiments performed on amnioblasts of one affected fetus from family 3 showed that primary cilia assembly was severely impaired, and that cytokinesis was also affected. In conclusion, our study describes novel forms of skeletal dysplasia associated with biallelic variants in KIF24. To our knowledge this is the first report implicating KIF24 variants as the cause of a skeletal dysplasia, thereby extending the genetic heterogeneity and the phenotypic spectrum of rare bone disorders and underscoring the wide range of monogenetic skeletal ciliopathies. (c) 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

To provide the initial confirmation of the c.1772CT (p.Ser591Phe) mutation in the transforming growth factor-Ophthalmologic examination of the proband was performed with slit lamp biomicroscopy. Saliva was collected as a source of DNA for screening all 17 exons ofSlit lamp examination of the 38-year-old proband revealed a clear cornea right eye and unilateral, discrete, and branching lattice lines in the anterior and mid-stroma of the central cornea left eye. Screening ofThe p.Ser591Phe mutation in

The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and cell types and provide human genetic evidence that TAAD is a non-atherosclerotic aortic disorder distinct from other forms of vascular disease. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and that it is not solely inherited through protein-altering variants of large effect size.

Individuals with specific language impairment (SLI) struggle with language acquisition despite average non-verbal intelligence and otherwise typical development. One SLI account focuses on grammar acquisition delay. The current study aimed to detect novel rare genetic variants associated with performance on a grammar assessment, the Test of Early Grammatical Impairment (TEGI), in English-speaking children. The TEGI was selected due to its sensitivity and specificity, consistently high heritability estimates, and its absence from all but one molecular genetic study. We performed whole exome sequencing (WES) in eight families with SLI (n = 74 total) and follow-up Sanger sequencing in additional unrelated probands (n = 146). We prioritized rare exonic variants shared by individuals with low TEGI performance (n = 34) from at least two families under two filtering workflows: (1) novel and (2) previously reported candidate genes. Candidate variants were observed on six new genes (PDHA2, PCDHB3, FURIN, NOL6, IQGAP3, and BAHCC1), and two genes previously reported for overall language ability (GLI3 and FLNB). We specifically suggest PCDHB3, a protocadherin gene, and NOL6 are critical for ribosome synthesis, as they are important targets of SLI investigation. The proposed SLI candidate genes associated with TEGI performance emphasize the utility of precise phenotyping and family-based genetic study.

BACKGROUND: Variants in RCBTB1 were recently described to cause a retinal dystrophy with only eight families described to date and a predominant phenotype of macular atrophy and peripheral reticular degeneration. Here, we further evaluate the genotypic and phenotypic characteristics of biallelic RCBTB1-associated retinal dystrophy in a North American clinic population. METHODS: A retrospective analysis of genetic and clinical features was performed in individuals with biallelic variants in RCBTB1. RESULTS: Three unrelated individuals of French-Canadian descent with rare biallelic RCBTB1 variants were identified. All individuals shared a novel p.(Ser342Leu) missense variant; one patient was homozygous whereas the other two each possessed a second unique novel variant p.(Gln120*) and p.(Pro224Leu). All three had macular-predominant disease with symptom onset in the fifth decade of life. CONCLUSION: This report adds to the genetic diversity of RCBTB1-associated disease. These cases confirm the later-onset, relative to many other retinal dystrophies, and macular focus of disease described in most cases to-date. They are thus a reminder of considering hereditary disease in the differential for later-onset macular atrophy.

A number of genes have been implicated in rare familial syndromes which have migraine as part of their phenotype but these genes have not previously been implicated in the common form of migraine.Among exome-sequenced participants in the UK Biobank, we identified 7194 migraine cases with the remaining 193,433 participants classified as controls. We investigated rare variants in 10 genes previously reported to be implicated in conditions with migraine as a prominent part of the phenotype and carried out gene- and variant-based tests for association.We found no evidence for association of these genes or variants with the common form of migraine seen in our subjects. In particular, a frameshift variant in KCNK18, p.(Phe139Trpfs*24), which had been shown to segregate with migraine with aura in a multiply affected pedigree, was found in 196 (0.10%) controls as well as in 10 (0.14%) cases (χSince there is no other reported evidence to implicate KCNK18, we conclude that this gene and its product, TRESK, should no longer be regarded as being involved in migraine aetiology. Overall, we do not find that rare, functional variants in genes previously implicated to be involved in familial syndromes including migraine as part of the phenotype make a contribution to the commoner forms of migraine observed in this population.

Hereditary neurological disorders (HNDs) are a clinically and genetically heterogeneous group of disorders. These disorders arise from the impaired function of the central or peripheral nervous system due to aberrant electrical impulses. More than 600 various neurological disorders, exhibiting a wide spectrum of overlapping clinical presentations depending on the organ(s) involved, have been documented. Owing to this clinical heterogeneity, diagnosing these disorders has been a challenge for both clinicians and geneticists and a large number of patients are either misdiagnosed or remain entirely undiagnosed. Contribution of genetics to neurological disorders has been recognized since long; however, the complete picture of the underlying molecular bases are under-explored. The aim of this study was to accurately diagnose 11 unrelated Pakistani families with various HNDs deploying NGS as a first step approach. Using exome sequencing and gene panel sequencing, we successfully identified disease-causing genomic variants these families. We report four novel variants, one each in, ECEL1, NALCN, TBR1 and PIGP in four of the pedigrees. In the rest of the seven families, we found five previously reported pathogenic variants in POGZ, FA2H, PLA2G6 and CYP27A1. Of these, three families segregate a homozygous 18 bp in-frame deletion of FA2H, indicating a likely founder mutation segregating in Pakistani population. Genotyping for this mutation can help low-cost population wide screening in the corresponding regions of the country. Our findings not only expand the existing repertoire of mutational spectrum underlying neurological disorders but will also help in genetic testing of individuals with HNDs in other populations.

The etiology of bipolar disorder (BD) is poorly understood. Considering the complexity of BD, pedigree-based sequencing studies focusing on haplotypes at specific loci may be practical to discover high-impact risk variants. This study comprehensively examined the haplotype sequence at 1p36-35 BD and recurrent depressive disorder (RDD) susceptibility loci.We surveyed BD families in Okinawa, Japan. We performed linkage analysis and determined the phased sequence of the affected haplotype using whole genome sequencing. We filtered rare missense variants on the haplotype. For validation, we conducted a case-control genetic association study on approximately 3000 Japanese subjects.We identified a three-generation multiplex pedigree with BD and RDD. Strikingly, we identified a significant linkage with mood disorders (logarithm of odds [LOD] = 3.61) at 1p36-35, supported in other ancestry studies. Finally, we determined the entire sequence of the 6.4-Mb haplotype shared by all affected subjects. Moreover, we found a rare triplet of missense variants in the SPOCD1 gene on the haplotype. Notably, despite the rare frequency, one heterozygote with multiple SPOCD1 variants was identified in an independent set of 88 BD type I genotyping samples.The 1p36-35 sequence was obtained from only a single pedigree. The replicate sample was small. Short-read sequencing might miss structural variants. A polygenic risk score was not analyzed.The 1p36-35 haplotype sequence may be valuable for future BD variant studies. In particular, SPOCD1 is a promising candidate gene and should be validated.

Context Synonymous mutations are usually nonpathogenic. Objective We report here a family with X-linked hypophosphatemia (XLH) due to a novel synonymous PHEX variant with a unique mechanism. Methods We studied a 4-member family (a mother, a son, and 2 daughters), all affected with XLH. Genomic DNA was extracted from peripheral leucocytes. Whole exome sequencing (WES) was used to identify the underlying genetic variant in the proband (the son). Sanger sequencing was used to confirm this variant in the proband and his family members. RT-PCR and sequencing of the cDNA revealed the effect of this variant on the PHEX structure and function Results A synonymous variant in the PHEX gene (c.1701A>C) was identified in all affected members. This variant changes the first nucleotide of exon 17 from adenine to cytosine. Using RT-PCR, this variant was shown to interfere with splicing of exons 16 with 17 resulting in a single shorter PHEX transcript in the proband compared to normal control. Sanger sequencing of the cDNA revealed a complete skipping of exon 17 and direct splicing of exons 16 and 18. This led to a frameshift and an introduction of a new stop codon in the next codon (codon 568), which ultimately led to truncation and loss of the final 183 amino acids of PHEX. Conclusion This novel variant shows how a synonymous exonic mutation may induce a complex series of changes in the transcription and translation of the gene and causes a disease, a mechanism that is not commonly recognized.

Oculocutaneous albinism (OCA) is a rare condition characterized by hypopigmentation. A female proband and her sister, both with primary amelanotic/hypopigmented melanoma, underwent three-dimensional total-body photography and dermoscopy. Both sisters had exome sequencing along with their brother, who had OCA but no history of melanoma. Imaging analysis was consistent with OCA in terms of individual typology angle scores, degree of sun damage, and high naevus counts. Exome data filtered for variants in known OCA and melanoma/naevi susceptibility genes (n = 98) found all siblings were compound heterozygous for TYR mutations (Arg402Ter and Val275Phe), previously reported as causative OCA variants. A rare missense variant in PARP1 (p.Pro377Ser) was solely present in the melanoma-unaffected brother, which is noteworthy as this was previously reported as potentially protective in a familial melanoma pedigree positive for CDKN2A mutations. Evaluation and confirmation of functional impact in larger cohorts could personalize melanoma screening in OCA.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE; OMIM 603041) is a rare inherited metabolic disorder mostly caused by mutations in TYMP gene encoding thymidine phosphorylase (TP) protein that affects the mitochondrial nucleotide metabolism. TP, functionally active as a homodimer, is involved in the salvage pathway of pyrimidine nucleosides. MNGIE-like syndrome having an overlapping phenotype of MNGIE was also described and has been associated with mutations in POLG and RRM2B genes. In the present study, we report the molecular investigation of a consanguineous family including two patients with clinical features suggestive of MNGIE syndrome. Bioinformatics analyses were carried out in addition to mtDNA deletion screening and copy number quantification in the blood of the two patients. Whole exome sequencing and Sanger sequencing analyses revealed the segregation in the affected family a novel mutation c.1205TA (p.L402Q) within the exon 9 of the TYMP gene. In addition, mtDNA analysis revealed the absence of mtDNA deletions and a decrease of the copy number in the blood of the two patients of the studied family. The p.Leu402Gln mutation was located in a conserved amino acid within the α/β domain of the TP protein and several software supported its pathogenicity. In addition, and based on docking and molecular dynamic simulation analyses, results revealed that L402Q caused a conformational change in TP mutated structure and could therefore alter its flexibility and stability. These changes prevent also the formation of stable homodimer leading to non-functional protein with partial or complete loss of its catalytic activity.

Autosomal recessive non-syndromic hearing loss (ARNSHL) is the most common hereditary deafness. It is genetically highly heterogeneous and about 89 gene loci and 76 gene's mutations have been implicated in the etiology of ARNSHL. Molecular basis of ARNSHL remains unresolved in 60% of cases and gene mutations are unknown for 23 of 89 reported loci. Techniques used to identify reported ARNSHL gene mutations can be divided into position-dependent and position-independent approaches. The localization of the loci has been facilitated by homozygosity mapping or linkage studies using STR or SNP genotyping in large consanguineous families. First few genes identified for hearing loss exhibited such wide diversity of function and expression patterns that candidate gene approach was not a viable option. The mapping of the disorder to a chromosomal location has been followed by Sanger sequencing of all genes in the target region or confining of the massively parallel sequencing data analyses to the linkage region. Sometimes genes located in the linkage interval were prioritized because there was a reported orthologs with mutations causing hearing loss in mouse or when mutations in the gene caused a related disorder. Position-independent approaches involving use of mouse subtractive cochlear libraries, forward genetic screening, and position-independent analyses of massively parallel sequencing data have helped identify 17 of 68 reported ARNSHL gene mutations. A thorough study of the strategies used in the identification of reported ARNSHL genes and of their relative success can help increase the success rate of future studies.

Neurodevelopmental disorder with microcephaly, ataxia, and seizures (NEDMAS) syndrome is a rare neurodevelopmental disorder characterized by moderate intellectual disability (ID), thin body habitus, microcephaly, seizures, ataxia, muscle weakness, and speech impairment. So far, only two families with NEDMAS have been reported. We report the clinical and molecular characteristics of three unrelated Turkish families with four NEDMAS patients. Whole-exome sequencing was used to search for the disease-causing variant. The main manifestations of the probands are severe developmental delay and ID, thin body habitus, and severe hypotonia. Brain imaging revealed bilateral cerebral and cerebellar diffuse atrophy. Sequencing results showed that both patients carried a novel missense variant c.1196C>T (p.Thr399Met) in the seryl-tRNA synthetase gene. Our findings help expand the variant spectrum of NEDMAS and provide additional information for diagnosing cases with atypical features. © 2022 Lippincott Williams and Wilkins. All rights reserved.

Progressive encephalopathy with brain edema and/or leukoencephalopathy, PEBEL1, is a severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration associated with a febrile illness. PEBEL1 is a lethal encephalopathy caused by NAXE gene mutations. Here we report a 6-month-old boy with mitochondrial encephalomyopathy from a consanguineous family. Molecular analysis was performed using whole-exome sequencing followed by segregation analysis. In addition, in silico prediction tools and molecular dynamic approaches were used to predict the structural effect of the mutation. Furthermore, molecular docking of the substrate NADP in both wild-type and mutated NAXE protein was carried out. Molecular analysis revealed the presence of the novel homozygous mutation c.641 T A (p. Ile214Asn) in the NAXE gene, located at the NAD (P)H hydrate epimerase domain. In addition, bioinformatics analyses and molecular dynamics revealed that p. Ile214Asn mutation could affect the structure, stability, and compactness of the NAXE protein. Moreover, the result of the molecular docking showed that the p. Ile214Asn mutation leads to conformational changes in the catalytic cavity, thus modifying interaction with the substrate and restricting its access. We also compared the phenotype of our patient with those of previously reported cases with PEBEL syndrome. All bioinformatics findings provide evidence that the NAXE variant Asn214 disrupts NAXE protein functionality leading to an insufficient NAD (P)HX repair system and the development of clinical features of PEBEL1 syndrome in our patient. To our knowledge, our case is the 21st case of PEBEL1 patient worldwide and the first case in North Africa.

This study aimed to establish which worldwide population cohorts have a genetic make-up closest to that of a large sample of the Maltese population with regard to corneal dystrophy (CD) genes.Single nucleotide polymorphisms (SNPs) in the Maltese cohort were compared with worldwide cohorts. Fixation index (FFIdentifying populations with least genetic differentiation can facilitate and help guide future diagnostic and treatment strategies for Maltese individuals with CDs in the absence of comparable Maltese data. Analysing the previously unknown CD genetic pool present in a large Maltese cohort adds to the global genetic bank that researchers rely on for medical progress.

Oculopharyngodistal myopathy (OPDM) is an adult-onset neuromuscular disease characterized by progressive ptosis, dysarthria, ophthalmoplegia, and distal muscle weakness. Recent studies revealed that GGC repeat expansions in 5'-UTR of LRP12, GIPC1, and NOTCH2NLC are associated with OPDM. Despite these advances, approximately 30% of OPDM patients remain genetically undiagnosed. Herein, we aim to investigate the genetic basis for undiagnosed OPDM patients in two unrelated Chinese Han families.Parametric linkage analysis was performed. Long-read sequencing followed by repeat-primed polymerase chain reaction and amplicon length polymerase chain reaction were used to determine the genetic cause. Targeted methylation sequencing was implemented to detect epigenetic changes. The possible pathogenesis mechanism was investigated by quantitative polymerase chain reaction, immunoblotting, RNA fluorescence in situ hybridization, and immunofluorescence staining of muscle biopsy samples.The disease locus was mapped to 12q24.3. Subsequently, GGC repeat expansion in the promoter region of RILPL1 was identified in six OPDM patients from two families, findings consistent with a founder effect, designated as OPDM type 4. Targeted methylation sequencing revealed hypermethylation at the RILPL1 locus in unaffected individuals with ultralong expansion. Analysis of muscle samples showed no significant differences in RILPL1 mRNA or RILPL1 protein levels between patients and controls. Public CAGE-seq data indicated that alternative transcription start sites exist upstream of the RefSeq-annotated RILPL1 transcription start site. Strand-specific RNA-seq data revealed bidirectional transcription from the RILPL1 locus. Finally, fluorescence in situ hybridization/immunofluorescence staining showed that both sense and antisense transcripts formed RNA foci, and were co-localized with hnRNPA2B1 and p62 in the intranuclear inclusions of OPDM type 4 patients.Our findings implicate abnormal GGC repeat expansions in the promoter region of RILPL1 as a novel genetic cause for OPDM, and suggest a methylation mechanism and a potential RNA toxicity mechanism are involved in OPDM type 4 pathogenesis. ANN NEUROL 2022;92:512-526.

The objective of this study was to estimate inbreeding coefficients in Holstein dairy cattle using imputed SNPs data. A data set of 95,540 Italian Holstein dairy cows from the routine genomic evaluations of the Italian National Association of Holstein, Brown, and Jersey Breeders were analyzed, with 84,445 imputed SNP. Ten widely used genomic inbreeding estimators were tested, including 4 PLINK v1.9 estimators (F, F

Childhood-onset forms of hereditary spastic paraplegia are ultra-rare diseases and often present with complex features. Next-generation-sequencing allows for an accurate diagnosis in many cases but the interpretation of novel variants remains challenging, particularly for missense mutations. Where sufficient knowledge of the protein function and/or downstream pathways exists, functional studies in patient-derived cells can aid the interpretation of molecular findings. We here illustrate the case of a 13-year-old female who presented with global developmental delay and later mild intellectual disability, progressive spastic diplegia, spastic-ataxic gait, dysarthria, urinary urgency, and loss of deep tendon reflexes of the lower extremities. Exome sequencing showed a novel splice-site variant in trans with a novel missense variant in B4GALNT1 [NM_001478.5: c.532-1GC/c.1556GC (p.Arg519Pro)]. Functional studies in patient-derived fibroblasts and cell models of GM2 synthase deficiency confirmed a loss of B4GALNT1 function with no synthesis of GM2 and other downstream gangliosides. Collectively these results established the diagnosis of B4GALNT1-associated HSP (SPG26). Our approach illustrates the importance of careful phenotyping and functional characterization of novel gene variants, particularly in the setting of ultra-rare diseases, and expands the clinical and molecular spectrum of SPG26, a disorder of complex ganglioside biosynthesis.

Presenilin 1 (PSEN1) mutations are a major cause of familial Alzheimer's disease. The pathogenic variant, PSEN1 p.G417S, has been reported to be associated with spastic paraparesis and cotton wool plaques in Japan. Here, we report a 3 generation Chinese pedigree that included 10 patients presenting with early-onset and rapid progression of parkinsonism with cognitive impairment in their third or fourth decade of life. Three additional living patients developed different degrees of cognitive impairment, without movement disorders. Magnetic resonance imaging of the brain showed white matter hyperintensities, multiple microbleeds, and enlarged perivascular spaces. Whole exome sequencing analysis of the proband detected the mutation, p.G417S, in PSEN1, which was completely co-segregated with the disease phenotype within the family by Sanger sequencing. 3D protein structures predicted that the mutation might influence contact with the lipid membrane and the interaction with beta-catenin. Our study provides insights into the heterogeneity in clinical presentation and imaging associated with mutations in PSEN1.

Isolated sulfite oxidase deficiency (ISOD) is a rare type of life-threatening neurometabolic disorders characterized by neonatal intractable seizures and severe developmental delay with an autosomal recessive mode of inheritance. Germline mutation in SUOX gene causes ISOD. Till date, only 32 mutations of SUOX gene have been identified and reported to be associated with ISOD.Here, we investigated a 5-days old Chinese female child, presented with intermittent tremor or seizures of limbs, neonatal encephalopathy, subarachnoid cyst and haemorrhage, dysplasia of corpus callosum, neonatal convulsion, hyperlactatemia, severe metabolic acidosis, hyperglycemia, and hyperkalemia.Whole exome sequencing identified a novel homozygous transition (c.1227G A) in exon 6 of the SUOX gene in the proband. This novel homozygous variant leads to the formation of a truncated sulfite oxidase (p.Trp409*) of 408 amino acids. This variant causes partial loss of the dimerization domain of sulfite oxidase. Hence, it is a loss-of-function variant. Proband's father and mother is carrying this novel variant in a heterozygous state. This variant was not found in 200 ethnically matched normal healthy control individuals.Our study not only expanded the mutational spectrum of SUOX gene associated with ISOD, but also strongly suggested the significance of whole exome sequencing for identifying candidate genes and novel disease-causing variants.

Sensorineural hearing loss is the most common sensory disorder in humans. Genetic analyses have greatly increased our understanding of the pathogenic mechanisms in play. Thus, characterization of audiologic phenotypes by the genetic etiology may aid elucidation of the etiologies of certain types of inherited hearing loss. Further, delineation of specific audiologic phenotypes based on the genetic etiology aids our understanding of some types of inherited hearing loss in terms of the prediction of clinical course, revelation of genotype-phenotype correlations, and application of appropriate audiologic rehabilitation. Here, we describe the interesting audiologic characteristics of LMX1A -associated deafness, which revealed significant asymmetry between two ears.Among 728 probands of which genomic DNA went through exome sequencing regardless of any specific audiologic phenotypes, probands for which exome sequencing was performed and a causative LMX1A variant was found were all included. Five LMX1A -associated DFNA7 families (approximately 0.7%), the pedigrees of whom indicated autosomal-dominant hearing loss, were identified, and segregation was studied using Sanger sequencing. The affected individuals underwent comprehensive evaluations, including medical history reviews, physical examinations, imaging, and auditory phenotyping. We functionally characterized the novel LMX1A variants via computational structural modeling and luciferase reporter assays.Among 728 probands of which genomic DNA went through exome sequencing, we identified four novel LMX1A heterozygous variants related to DFNA7 (c.622CT:p.Arg208*, c.719AG:p.Gln240Arg, c.721GA:p.Val241Met, and c.887dup:p.Gln297Thrfs*41) and one harboring a de novo heterozygous missense LMX1A variant (c.595AG;p.Arg199Gly) previously reported. It is important to note that asymmetric hearing loss was identified in all probands and most affected individuals, although the extent of asymmetry varied. Structural modeling revealed that the two missense variants, p.Gln240Arg and p.Val241Met, affected conserved residues of the homeodomain, thus attenuating LMX1A-DNA interaction. In addition, Arg208*-induced premature termination of translation destroyed the structure of the LMX1A protein, including the DNA-binding homeodomain, and p.Gln297Thrfs*41 led to the loss of the C-terminal helix involved in LIM2 domain interaction. Compared with the wild-type protein, all mutant LMX1A proteins had significantly reduced transactivation efficiency, indicating that the ability to elicit transcription of the downstream target genes of LMX1A was severely compromised. Thus, in line with the American College of Medical Genetics and Genomics guideline specified to genetic hearing loss, the four novel LMX1A variants were identified as "pathogenic" (p.Arg208* and p.Gln297Thrfs*41), "likely pathogenic" (p.Val241Met), and as a "variant of uncertain significance'' (p.Gln240Arg).For the first time, we suggest that LMX1A is one of the candidate genes which, if altered, could be associated with dominantly inherited asymmetric hearing loss. We also expand the genotypic spectrum of disease-causing variants of LMX1A causing DFNA7 by doubling the number of LMX1A variants reported thus far in the literature.

Focal facial dermal dysplasias type III (FFDD III), commonly known as Setleis syndrome (SS; Online Mendelian Inheritance in Man #227260), is a type of focal facial dermal dysplasia, characterized by bitemporal atrophic skin lesion. The homozygous mutations in the TWIST2 gene and copy number variants (CNV) at chromosome 1p36.22p36.21 were reported as the pathogenic mechanism. In this study, we collected DNA samples from a large Chinese family affected by FFDD and found no mutation of TWSIT2. To determine the underlying genetic cause, we performed a multipoint parameter linkage analysis and haplotype analysis of the family 1 and mapped SS to a region Chr1:14.074-20.524cM (rs2401090-rs2294642). Copy number variant was identified by Sanger sequencing, which breakpoints were Chr1:11695972 and Chr1:11829858. The region contains eight genes, including FBXO2, FBXO44, FBXO6, MAD2L2, DRAXIN, AK125437, AGTRAP, and C1orf167. There were no candidate gene mutations of the second family with SS. Our study further reduced the size of CNV resulting in SS (Chr1:11696993-11829858) and focused on eight genes.

In this study, we aimed to determine the genetic basis of a Turkish family related to hereditary spastic paraplegia (HSP) by exome sequencing. HSP is a progressive neurodegenerative disorder and displays genetic and clinical heterogeneity. The major symptoms are muscle weakness and spasticity, especially in the lower extremities. We studied seven affected and seven unaffected family members, as well as a clinically undetermined member, to identify the disease-causing gene. Exome sequencing was performed for four affected and two unaffected individuals. The variants were firstly filtered for HSP-associated genes, and we found a common variant in the ZFYVE27 gene, which has been previously implied for association with HSP. Due to the incompletely penetrant segregation pattern of the ZFYVE27 variant, revealed by Sanger sequencing, with the disease in this family, filtering was re-performed according to the mode of inheritance and allelic frequencies. The resulting 14 rare variants were further evaluated in terms of their cellular functions, and three candidate variants in ATAD3C, VPS16, and MYO1H genes were selected as possible causative variants, which were analyzed for their familial segregation. ATAD3C and VPS16 variants were eliminated due to incomplete penetrance. Eventually, the MYO1H variant NM_001101421.3:c.2972_2974del (p.Glu992del, rs372231088) was found as the possible disease-causing deletion for HSP in this family. This is the first study reporting the possible role of a MYO1H variant in HSP pathogenesis. Further studies on the cellular roles of Myo1h protein are needed to validate the causality of MYO1H gene at the onset of HSP.

Objective Solute carrier family 19 member 2 (SLC19A2, OMIM *603941) encodes thiamine human transporter 1 (THTR-1), which contributes to bringing thiamine (vitamin B1) into cells. Mutations in SLC19A2 lead to a rare recessive genetic disorder termed thiamine-responsive megaloblastic anemia (TRMA) syndrome. Methods An Iranian family with TRMA was investigated by whole-exome sequencing (WES) to determine the genetic cause(s) of the disease. Accordingly, SLC19A2 genetic variants were gathered through literature analysis. Results WES recognized a known pathogenic variant, c.697C > T (p. Q233X), within exon 2 of SLC19A2 (NM_006996). Subsequently, the proband’s parents and sister were confirmed as heterozygous carriers of the identified variant. Conclusion The diagnostic utility and affordability of WES were confirmed as the first approach for the genetic testing of TRMA to verify the diagnosis. This analysis can be used to guide future prenatal diagnoses and determine the consequences in the other family members.

Leber's hereditary optic neuropathy (LHON), the most common mitochondrial optic neuropathy, causes visual loss, especially in young adults. Due to the absence of epidemiological data in Southeast Asia, we aimed to determine Thai LHON patients' characteristics (demographic data, mutation types, and prognoses) as the first study in this region.This retrospective chart review enrolled all Thai LHON patients confirmed by three mitochondrial DNA mutations (G11778A, T14484C, and G3460A) between January 1997 and December 2016. Patients with more than one year of follow-up were included in a visual progression analysis. The Mann-Whitney U-test was applied to compare groups, and prognosis-associated factors were analysed with the generalized estimating equation.In all, 229 patients were enrolled, with only nineteen females. Most mutations were of the G11778A type (91%), with T14484C accounting for the remainder. The age at onset of G11778A (21.9 years; interquartile range [IQR] 14.9, 33.5) was younger than that of T14484C (33.0 years; IQR 19.4, 37.5). Of 45 patients, the T14484C group demonstrated good vision recovery, whereas the G11778A group did not improve (difference in logMAR -0.7 and IQR -1.5, -0.2 versus logMAR 0.0 and IQR -0.3, 0.2, respectively;The leading mutation in Thai LHON patients is the G11778A missense, followed by T14484C, while G3460A was not detected. The vast majority of patients were young adult males. The G11778A mutation, older age, and male gender are associated with poor vision outcomes. Key messageThe G11778A missense mutation is the most common among Thai LHON patients, followed by T14484C, while G3460A was not found. The G11778A mutation, older age, and male gender are associated with poor vision outcomes.

Approximate multistep methods to calculate reliabilities for estimated breeding values in large genetic evaluations were developed for single-trait (ST-R

A genealogy of the United States has been record-linked to National Veteran's Health Administration (VHA) patient data to allow non-identifiable analysis of familial clustering. This genealogy, including over 70 million individuals linked to over 1 million VHA patients, is the largest such combined resource reported. Analysis of familial clustering among VHA patients diagnosed with Post Traumatic Stress Disorder (PTSD) allowed a test of the hypothesis of an inherited contribution to PTSD. PTSD is associated strongly with military service and extended familial clustering data have not previously been presented. PTSD-affected VHA patients with genealogy data were identified by presence of an ICD diagnosis code in the VHA medical record in at least 2 different years. The Genealogical Index of Familiality (GIF) method was used to compare the average relatedness of VHA patients diagnosed with PTSD with their expected average relatedness, estimated from randomly selected sets of matched linked VHA patient controls. Relative risks for PTSD were estimated in first-, second-, and third-degree relatives of PTSD patients who were also VHA patients, using sex and age-matched rates for PTSD estimated from all linked VHA patients. Significant excess pairwise relatedness, and significantly elevated risk for PTSD in first-, second-, and third-degree relatives was observed; multiple high-risk extended PTSD pedigrees were identified. The analysis provides evidence for excess familial clustering of PTSD and identified high-risk PTSD pedigrees. These results support an inherited contribution to PTSD predisposition and identify a powerful resource of high-risk PTSD pedigrees for predisposition gene identification.

The phenotype of North Carolina macular dystrophy (NCMD) is highly variable and remains poorly appreciated and understood, often causing misdiagnoses in isolated cases. One of the features of NCMD is the general lack of progression despite its original name, "dominant progressive foveal dystrophy," as reported in 1971 by Lefler et al (W.H.L.). The purpose of this study was to report the long-term follow-up of this condition.Systematic, longitudinal, and detailed documentation along with the imaging of the peripheral retina.We reexamined 27 of the original family members with NCMD in an office setting 30 to 50 years after they were first reported.The evaluation of all the affected subjects included best-corrected visual acuity (BCVA), slit-lamp and dilated-fundus examinations, wide-field fundus and autofluorescent photography, and spectral-domain OCT (SD OCT). Blood was collected for DNA extraction, banking, and sequencing.Best-corrected visual acuity, slit-lamp and dilated-fundus examinations, wide-field fundus and autofluorescent photography, and SD OCT.The 27 subjects examined were a part of the original family with NCMD that was initially reported in 1971. A point mutation (NC_000006.11:g.100040906GT) (Hg19) in a noncoding region of a deoxyribonuclease I hypersensitivity binding site was found in all the affected subjects. Nine subjects were the affected children of those originally examined 30 to 50 years ago by Kent W. Small (K.W.S.) and W.H.L., and the remaining 17 subjects (34 eyes) had been examined 30 years previously by K.W.S. Of these 17 subjects (34 eyes), 4 of 34 (11%) eyes showed worsening of vision and evidence of fibrosis due to choroidal neovascular membranes (CNVMs). Fourteen of the 27 (51%) patients showed peripheral retinal drusen, which did not seem to correlate with the severity of the macular disease.Most patients with NCMD have stable vision and fundus findings throughout their lives. The ones who experienced BCVA decline did so because of the apparent evidence of CNVMs. Patients with grade 2 NCMD seem to be at an increased risk of further or progressive vision loss due to CNVMs. Intravitreal therapy with vascular endothelial growth factor inhibitors may benefit these patients if they are treated in a timely fashion. Peripheral retina drusen of varying degrees of severity were found in slightly more than half of the affected subjects.

This study aimed to provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids program.Extensive analyses of 960 families with suspected genetic disorders included short-read exome sequencing and short-read genome sequencing (srGS); PacBio HiFi long-read genome sequencing (HiFi-GS); variant calling for single nucleotide variants (SNV), structural variant (SV), and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants, and pedigrees were stored in PhenoTips database, with data sharing through controlled access the database of Genotypes and Phenotypes.Diagnostic rates ranged from 11% in patients with prior negative genetic testing to 34.5% in naive patients. Incorporating SVs from genome sequencing added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with4-fold more rare coding SVs compared with srGS. Variants and genes of unknown significance remain the most common finding (58% of nondiagnostic cases).Computational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated using HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation and by providing HiFi variant (SNV/SV) resources from1000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.

Clinical phenotypes of a patient with a deletion of the entire

The mounting increase in the technological complexity of modern engineering systems requires compound uncertainty quantification, from a quantitative and qualitative perspective. This paper presents a Compound Uncertainty Quantification and Aggregation (CUQA) framework to determine compound outputs along with a determination of the greatest uncertainty contribution via global sensitivity analysis. This was validated in two case studies: a bespoke heat exchanger test rig and a simulated turbofan engine. The results demonstrated the effective measurement of compound uncertainty and the individual impact on system reliability. Further work will derive methods to predict uncertainty in-service and the incorporation of the framework with more complex case studies.

We assessed the performance of single-step genomic prediction of breeding values for superovulatory response traits in Japanese Black donor cows. A total of 25,332 records of the total number of embryos and oocytes (TNE) and the number of good embryos (NGE) per flush for 1874 Japanese Black donor cows were collected during 2008 and 2022. Genotype information on 36,426 autosomal single-nucleotide polymorphisms (SNPs) for 575 out of the 1,874 cows was used. Breeding values were predicted exploiting a two-trait repeatability animal model. Two genetic relationship matrices were used, one based on pedigree information (A matrix) and the other considering both pedigree and SNP marker genotype information (H matrix). Estimated heritabilities of TNE and NGE were 0.18 and 0.11, respectively, when using the H matrix, which were both slightly lower than when using the A matrix (0.26 for TNE and 0.16 for NGE). Estimated genetic correlations between the traits were 0.61 and 0.66 when using H and A matrices, respectively. When the variance components were the same in breeding value prediction, the mean reliability was greater when using the H matrix than when using the A matrix. This advantage seems more prominent for cows with low reliability when using the A matrix. The results imply that introducing single-step genomic prediction could boost the rate of genetic improvement of superovulatory response traits, but efforts should be made to maintain genetic diversity when performing selection.

GEMIN5 is a multifunctional RNA-binding protein required for the assembly of survival motor neurons. Several bi-allelic truncating and missense variants in this gene are reported to cause a neurodevelopmental disorder characterized by cerebellar atrophy, intellectual disability (ID), and motor dysfunction. Whole exome sequencing of a Pakistani consanguineous family with three brothers affected by ID, cerebral atrophy, mobility, and speech impairment revealed a novel homozygous 3bp-deletion NM_015465.5:c.3162_3164del that leads to the loss of NM_015465.5 (NP_056280.2):p. (Asp1054_Ala1055delinsGlu) amino acid in one of the α-helixes of the tetratricopeptide repeats of GEMIN5. In silico 3D representations of the GEMIN5 dimerization domain show that this variant likely affects the orientation of the downstream sidechains out of the helix axis, which would affect the packing with neighboring helices. The phenotype of all affected siblings overlaps well with previously reported patients, suggesting that NM_015465.5: c.3162_3164del (NP_056280.2):p. (Asp1054_Ala1055delinsGlu) is a novel GEMIN5 pathogenic variant. Overall, our data expands the molecular and clinical phenotype of the recently described neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM) syndrome.

Background. Hereditary coproporphyria (HCP) is a rare autosomal dominant disorder caused by a partial deficiency of coproporphyrinogen III oxidase (CPOX), and systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic predisposition. SLC7A7 (solute carrier family 7 member 7) may be associated with monogenic lupus disease; however, only 2 cases of concomitant HCP and SLE have been reported. Methods. We report a 30-year-old woman with a six-year history of SLE presenting with abdominal pain, vomiting, dysuria, tachycardia, and hyponatremia. Whole exome sequencing (WES) and Sanger sequencing were carried out for the proband and members of her pedigree to detect the genetic background. The Gene Expression Omnibus (GEO) database was used to search the related gene expression profiles. Differentially expressed genes (DEGs) were identified using GEO2R. Result. A novel heterozygous splicing mutation of CPOX (NM_000097): c.700+2 T > C (intron 2) was detected by WES in the proband, and it was considered likely pathogenic (PSV1+PM2). Sanger sequencing verified the heterozygous mutation of CPOX in the proband, although it was not detected in her father. WES also identified 62 other gene variants, especially two heterozygous variants in SLC7A7 (NM_001126106): c.250G > A (p. V84I) and c.625+1G > A (splicing). DEGs were detected from GSE51997, and the expression of CPOX was downregulated in SLE patients compared with normal controls (adj. P = 0.0071 , logFC = − 1.0975 ). Conclusion. This study presents the first reported case of SLE coexisting with HCP in China; moreover, a novel splicing mutation of CPOX, i.e., c.700+2 T > C (intron 2), and two heterozygous mutations of SLC7A7 were reported. The simultaneous mutations of CPOX and SLC7A7 may explain the etiopathogenetic connections of HCP and SLE.