Human sulfotransferase SULT2B1 physiological role and the impact of genetic polymorphism on enzyme activity and pathological conditions.

Human SULT2B1gene is responsible for expressing SULT2B1a and SULT2B1b enzymes, which are phase II metabolizing enzymes known as pregnenolone and cholesterol sulfotransferase (SULT), respectively. They are expressed in several tissues and contribute to steroids and hydroxysteroids homeostasis. Genetic variation of the SULT2B1 is reported to be associated with various pathological conditions, including autosomal recessive ichthyosis, cardiovascular disease, and different types of cancers. Understanding the pathological impact of SULT2B1 genetic polymorphisms in the human body is crucial to incorporating these findings in evaluating clinical conditions or improving therapeutic efficacy. Therefore, this paper summarized the most relevant reported studies concerning SULT2B1 expression, tissue distribution, substrates, and reported genetic polymorphisms and their mechanisms in enzyme activity and pathological conditions.

Autosomal recessive type of dystrophic epidermolysis bullosa with a novel variant in the COL7A1 gene.

Epidermolysis bullosa (EB) is an inherited skin condition whose hallmark is skin fragility caused by minimal trauma or friction. The dystrophic type of EB (DEB), accounting for 30% of all cases, is caused by mutations in the gene encoding type VII collagen α1 chain (COL7A1). It is inherited in an autosomal-dominant or autosomal-recessive manner. The clinical manifestations tend to be variable and frequently overlapping. Therefore, genetic testing is of great significance for establishing an exact genetic diagnosis. The present case study reports on a female patient with a clinical diagnosis of DEB, who had an inconclusive phenotype with no family history of DEB. Genetic analysis of the patient, via next-generation sequencing, revealed a compound heterozygous state for the COL7A1 gene. Segregation analysis revealed the parental origin of both variants-a missense variant [c.6022C>T p.(Arg2008Cys)] inherited from the father and a novel frameshift variant [c.3474del p.(Val1160Ter)] inherited from the mother. The established result assigned an exact genetic diagnosis and type of inheritance and allowed the personalization of the genetic counseling for this patient with regard to prognosis and future reproduction.

Sex-specific viability effects of mutations in Drosophila melanogaster.

In populations with separate sexes, genetic load due to deleterious mutations may be expressed differently in males and females. Evidence from insect models suggests that selection against mutations is stronger in males. This pattern will reduce deleterious allele frequencies at the expense of males, such that female mean fitness is greater than expected, preserving population persistence in the face of high mutation rates. While previous studies focus on reproductive success, mutation load depends on total selection in each sex, including selection for viability. We might expect minimal sex differences in viability effects in fruit flies, since male and female larvae behave similarly, yet many genes show sex-biased expression in larvae. We measured the sex-specific viability effects of nine "marker" mutations and 123 mutagenized chromosomes. We find that both types of mutations generally reduce viability in both sexes. Among marker mutations we detect instances of sex biased effects in each direction; mutagenized chromosomes show little sex-specific mutational variance, but recessive lethals show a female bias, including in FlyBase records. We conclude that mutations regularly affect viability in a sex-specific manner, but that the strong pattern of male-biased mutational effects observed previously for reproductive success is not apparent at the pre-reproductive stage.

[Autosomal recessive polycystic kidney disease in a girl]. / å¸¸æŸ“è‰²ä½“éšæ€§é—ä¼ æ€§å¤šå›Šè‚¾1例.

A 5-year-old girl was admitted due to one episode of melena and one episode of hematemesis. Upon admission, gastroscopy revealed esophageal and gastric varices. Abdominal CT scan, MRI, and color Doppler ultrasound suggested cirrhosis, intrahepatic bile duct dilation, and bilateral kidney enlargement. Genetic testing identified compound heterozygous mutations in the PKHD1 gene: c.2264C>T (p.Pro755Leu) and c.1886T>C (p.Val629Ala). The c.2264C>T (p.Pro755Leu) mutation is a known pathogenic variant with previous reports, while c.1886T>C (p.Val629Ala) is a novel mutation predicted to have pathogenic potential according to Mutation Taster and PolyPhen2. The child was diagnosed with autosomal recessive polycystic kidney disease. In children presenting with gastrointestinal bleeding without obvious causes, particularly those with liver or kidney disease, consideration should be given to the possibility of autosomal recessive polycystic kidney disease, and genetic testing should be conducted for definitive diagnosis when necessary.

Atypical Neuroimaging Findings in a Patient With Mucopolysaccharidosis Type VII (Sly Syndrome).

Mucopolysaccharidosis (MPS) consists of a heterogeneous group of multisystem disorders that are usually inherited. This spectrum consists of seven subtypes in total. Sly syndrome, also known as type VII MPS, is a multisystem disorder with a wide array of symptoms that overlap with other mucopolysaccharide disorders. Diagnosis of Sly syndrome relies on metabolic and radiological criteria. This report presents a case of a 19-year-old male who presented with seizures as his chief complaint. By metabolic workup done previously, he was diagnosed with Sly syndrome, an autosomal recessive mucopolysaccharide syndrome. This case underscores various multisystem features associated with the disease; however, it mainly highlights and emphasizes the diverse neurological features, including typical and atypical neuroimaging in Sly syndrome, aiding in its characterization, early diagnosis, and management.

Clinico-genetic profile of seven patients with PARK-PINK1: A case series from a tertiary care centre from India and review of literature.

Background: Recessive variants in the PINK1 gene is a known cause of early-onset Parkinson's disease (EOPD). Objective: To describe the clinical features and genetic profile of patients of PARK-PINK1. Methods: Retrospective chart review of demographic, clinical and genetic details of patients carrying biallelic PINK1 variants from our database. Result: Seven cases were recruited with median age at onset 33 years (Range: 20-49). All had asymmetrical onset, tremor in four, abnormal posturing in two and slowness in one patient. Parkinsonism phenotype was noted in six patients (with dystonia in four) and isolated dystonia in one. Among 6 patients with parkinsonism, five had rest tremor, all had good levodopa-response, and four had motor-fluctuation with choreiform-dyskinesia. Exome-sequencing revealed bi-allelic pathogenic/likely pathogenic variants in all of which five were novel. Conclusion: PARK-PINK1 presents as an EOPD with tremor-predominant phenotype, good levodopa-responsiveness, early motor fluctuation and dyskinesia. We describe five novel variants in PINK1 gene.

Autosomal recessive hypophosphatemic rickets type 2 due to ENPP1 deficiency (ARHR2).

Autosomal recessive hypophosphatemic rickets type 2 (ARHR2; MIM #613312) is a very rare disorder caused by biallelic loss-of-function mutations in the ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) gene. ENPP1 deficiency encompasses a spectrum of phenotypes that includes, in addition to ARHR2, generalized arterial calcification of infancy (GACI), ossification of the posterior longitudinal ligament (OPLL), and pseudoxanthoma elasticum. ARHR2 can be found in GACI survivors, but it may also be the first manifestation of ENPP1 deficiency. Although the precise mechanisms are not fully elucidated, patients with GACI and ARHR2 have elevated serum FGF23 levels, leading to renal phosphate wasting and hypophosphatemia. As a result, the clinical and radiological phenotype of ARHR2 patients is very similar to that of patients affected with other forms of hypophosphatemic rickets, such as X-linked hypophosphatemia. Patients show signs of rickets (abnormal mineralization of growth plates in children) and osteomalacia (abnormal bone mineralization in children and adults) of varying severity. Clinical manifestations specific to ENPP1 loss-of-function mutations and common to GACI, such as ectopic calcifications (valvular, arterial, or periarticular), deafness, OPLL, and PXE, may also be found. Genetic confirmation of the disease is important so as to ensure that patients receive the appropriate treatment or have the opportunity to participate in clinical trials to evaluate the safety and efficacy of novel and promising recombinant enzyme therapies.

Severe Phenotype With RECQL4 Syndrome: A Report of Two Cases.

Baller-Gerold syndrome (BGS, OMIM: 218600), RAPADILINO syndrome (OMIM 266280), and Rothmund-Thomson syndrome (RTS, OMIM 266280), which are caused in some cases by RECQL4 pathogenic variants, show autosomal recessive inheritance. Some refer to them collectively as RECQL4 syndromes. Most cases have been reported during infancy and childhood periods. However, there have been no reports of phenotypes resulting in a lethal course in the perinatal period. We identified two fetuses with biallelic RECQL4 pathogenic variants during the perinatal period. The two fetuses with RECQL4 syndrome showed structural abnormalities, including severely hypoplastic forearms and lower legs. One fetus also had severe pulmonary hypoplasia. One case resulted in neonatal death because of respiratory failure, and the other was artificially terminated during pregnancy. The RECQL4 pathogenic variants were identified by exome sequencing followed by Sanger sequencing. The biallelic RECQL4 pathogenic variants can induce a lethal skeletal disorder.

[BLIRD - a new genetic disease in Holstein cattle in Switzerland]. / BLIRD ­ eine neue genetische Erkrankung beim Holsteinrind in der Schweiz.

INTRODUCTION: Recently, a new hereditary disease, bovine lymphocyte intestinal retention defect (BLIRD), was discovered in Holstein cattle in France and is caused by a variant in the Integrin subunit beta 7 (ITGB7) gene. The altered cell adhesion molecule resulting from this point mutation is responsible for an impaired tissue of CD4 T lymphocytes from the blood to intestinal tissue. The aim of this study was to assess the allelic frequency of this deleterious variant in the local Holstein population and to clinically examine ten BLIRD-affected Holstein cattle from Switzerland in order to characterise the phenotype of this new hereditary disease, which is still unknown to the veterinary community. BLIRD was associated with severely impaired animal health in the rearing phase and significantly reduced animal welfare due to weakened immune defences, below-average development and recurrent diarrhoea. Further examinations revealed increased leucocyte values and a slightly increased average age at first calving. Affected homozygous animals are labelled internationally as BLIRD-carrier homozygous (LRS), BLIRD-carrier heterozygous (LRC) and BLIRD-free (LRF). An obvious inbreeding practice was clearly demonstrated by the pedigree analysis of the ten animals, which all trace back to the potential founder bull. Herein, BLIRD has been detected and described in Switzerland for the first time. The ITGB7 variant allele has a frequency of 2,1 % in the current Swiss Holstein population, which is below the level of the cholesterol deficiency (CD)-associated apolipoprotein B (APOB) variant allele with a frequency of 3,9 %. Although relatively rare, attention should be paid to the BLIRD genotype when mating in order to exclude further affected animals. In cattle with clinically suspected BLIRD, the diagnosis should be confirmed by genetic testing.

INTRODUCTION: Récemment, une nouvelle maladie héréditaire récessive, le défaut de rétention intestinale des lymphocytes bovins (bovine lymphocyte intestinal retention defect BLIRD), a été découverte chez les bovins Holstein en France. Elle est causée par une variante du gène Integrin subunit beta 7 (ITGB7). L'altération de la molécule d'adhésion cellulaire résultant de cette mutation ponctuelle est responsable de l'altération du transfert des lymphocytes T CD4 du sang vers le tissu intestinal. L'objectif de cette étude était d'évaluer la fréquence allélique de cette variante délétère dans la population Holstein locale et d'examiner cliniquement dix bovins Holstein suisses atteints de BLIRD afin de caractériser le phénotype de cette nouvelle maladie héréditaire, qui est encore inconnue de la communauté vétérinaire. La BLIRD a été associée à une grave détérioration de la santé des animaux pendant la phase d'élevage et à une réduction significative de leur bien-être en raison de l'affaiblissement des défenses immunitaires, d'un développement inférieur à la moyenne et de diarrhées récurrentes. Des examens complémentaires ont révélé une augmentation des valeurs leucocytaires et une légère augmentation de l'âge moyen au premier vêlage. Les animaux homozygotes affectés sont étiquetés au niveau international comme homozygotes porteurs de BLIRD (LRS), hétérozygotes porteurs de BLIRD (LRC) et exempts de BLIRD (LRF). Une pratique de consanguinité évidente a été clairement démontrée par l'analyse généalogique des dix animaux, qui remontent tous au taureau fondateur potentiel. La BLIRD a été ainsi détectée et décrite pour la première fois en Suisse. La allèle délétère ITGB7 a une fréquence de 2,1 % dans la population Holstein suisse actuelle, ce qui est inférieur au niveau de la allèle délétère de l'apolipoprotéine B (APOB) associée à la déficience en cholestérol (CD), dont la fréquence est de 3,9 %. Bien que relativement rare, il convient de prêter attention au génotype BLIRD lors de l'accouplement afin d'exclure de la reproduction d'autres animaux affectés.

Massive detection of cryptic recessive genetic defects in dairy cattle mining millions of life histories.

BACKGROUND: Dairy cattle breeds are populations of limited effective size, subject to recurrent outbreaks of recessive defects that are commonly studied using positional cloning. However, this strategy, based on the observation of animals with characteristic features, may overlook a number of conditions, such as immune or metabolic genetic disorders, which may be confused with pathologies of environmental etiology. RESULTS: We present a data mining framework specifically designed to detect recessive defects in livestock that have been previously missed due to a lack of specific signs, incomplete penetrance, or incomplete linkage disequilibrium. This approach leverages the massive data generated by genomic selection. Its basic principle is to compare the observed and expected numbers of homozygotes for sliding haplotypes in animals with different life histories. Within three cattle breeds, we report 33 new loci responsible for increased risk of juvenile mortality and present a series of validations based on large-scale genotyping, clinical examination, and functional studies for candidate variants affecting the NOA1, RFC5, and ITGB7 genes. In particular, we describe disorders associated with NOA1 and RFC5 mutations for the first time in vertebrates. CONCLUSIONS: The discovery of these many new defects will help to characterize the genetic basis of inbreeding depression, while their management will improve animal welfare and reduce losses to the industry.

Genome-Wide Association Studies and QTL Mapping Reveal a New Locus Associated with Resistance to Bacterial Pustule Caused by Xanthomonas citri pv. glycines in Soybean.

Bacterial pustule (BP), caused by Xanthomonas citri pv. glycines, is an important disease that, under favorable conditions, can drastically affect soybean production. We performed a genome-wide association study (GWAS) with a panel containing Brazilian and American cultivars, which were screened qualitatively and quantitatively against two Brazilian X. citri isolates (IBS 333 and IBS 327). The panel was genotyped using a genotyping by sequencing (GBS) approach, and we identified two main new regions in soybeans associated with X. citri resistance on chromosomes 6 (IBS 333) and 18 (IBS 327), different from the traditional rxp gene located on chromosome 17. The region on chromosome 6 was also detected by QTL mapping using a biparental cross between Williams 82 (R) and PI 416937 (S), showing that Williams 82 has another recessive resistance gene besides rxp, which was also detected in nine BP-resistant ancestors of the Brazilian cultivars (including CNS, S-100), based on haplotype analysis. Furthermore, we identified additional SNPs in strong LD (0.8) with peak SNPs by exploring variation available in WGS (whole genome sequencing) data among 31 soybean accessions. In these regions in strong LD, two candidate resistance genes were identified (Glyma.06g311000 and Glyma.18g025100) for chromosomes 6 and 18, respectively. Therefore, our results allowed the identification of new chromosomal regions in soybeans associated with BP disease, which could be useful for marker-assisted selection and will enable a reduction in time and cost for the development of resistant cultivars.

HTRA1-related cerebral small-vessel disease causes cerebral microbleeds on the brainstem surface.

BACKGROUND AND OBJECTIVES: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) has recently been known as HTRA1-related cerebral small-vessel disease (CSVD), it is caused by variants in HTRA1. Recently, it has been reported to develop in heterozygotes with some variants of the gene. Multiple prospective studies have reported that the frequency of heterozygous HTRA1 variants developing CSVD is 2 - 6.5 % in CARASIL. Heterozygous variant cases lack unique clinical features, have an older age of onset, and are difficult to detect. Characteristic findings are required to identify such cases. METHOD: Magnetic resonance imaging (MRI) images of cases that experienced cerebral infarction and carried heterozygous variants in HTRA1 were reviewed. RESULTS: Four cases of heterozygous HTRA1-related CSVD in two families (Family 1: c.754G > A, p.A252T; three males. Family 2: c.497G > T, p.R166L, one female). In all cases, white matter lesions with lacunar infarcts were observed in the periventricular and basal ganglia, external capsule, and brainstem. Moreover, T2 star weighted image (T2*WI) low presented dot-like lesions were present along the surface of the brainstem, which have only been reported in one homozygous case. Susceptibility-weighted imaging (SWI) was performed in two cases, and the dot-like lesions on T2*WI resembled a pearly tiara along the surface of the brainstem. CONCLUSION: Brainstem surface on T2*WI low showed dot-like lesions, which are not generally observed in patients with stroke and can be characteristic of HTRA1-CSVD associated with heterozygous variant. The pathology requires further investigation for diagnosis.

An infant case of autosomal recessive polycystic kidney disease-associated dilated cardiomyopathy-like hypertensive cardiomyopathy diagnosed because of urinary tract infection.

We report a case of dilated cardiomyopathy-like hypertensive cardiomyopathy (HTN-CM) with polycystic kidney disease without family history when a 3-month-old boy developed bacteraemia secondary to a urinary tract infection. He was later confirmed as having autosomal recessive inheritance due to the proven PKHD1 gene mutation. The treatment consisted mainly of antihypertensive and anti-heart failure therapies and he was discharged on the 131st day. To prevent the development of heart failure in patients with HTN-CM due to autosomal recessive polycystic kidney disease (ARPKD), it is important to improve the fetal diagnosis rate of ARPKD, detect hypertension early, and strictly control the blood pressure after birth.

Expanding MNS1 Heterotaxy Phenotype.

MNS1 (meiosis-specific nuclear structural protein-1 gene) encodes a structural protein implicated in motile ciliary function and sperm flagella assembly. To date, two different homozygous MNS1 variants have been associated with autosomal recessive visceral heterotaxy (MIM#618948). A French individual was identified with compound heterozygous variants in the MNS1 gene. A collaborative call was proposed via GeneMatcher to describe new cases with this rare syndrome, leading to the identification of another family. The first patient was a female presenting complete situs inversus and unusual symptoms, including severe myopia and dental agenesis of 10 permanent teeth. She was found to carry compound heterozygous frameshift and nonsense variants in MNS1. The second and third patients were sibling fetuses with homozygous in-frame deletion variants in MNS1 and homozygous missense variants in GLDN. Autopsies revealed a complex prenatal malformation syndrome. We add here new cases with the ultra-rare MNS1-related disorder and provide a review of all published individuals.

Bright and enlarged fetal kidneys: One phenotype different genotypes, and counseling dilemmas.

INTRODUCTION: In the present study we describe atypical cases with bright and enlarged fetal kidneys identified on fetal ultrasound with different genetic etiologies. METHODS: Exome sequencing was undertaken after prenatal counseling and after the initial diagnosis of enlarged fetal kidneys was made on ultrasound for four cases and the results were then correlated. RESULTS: In the present study we identified underlying variants in ACE, ETFA, PKD1, and MKS1 gene where the atypical presentation of fetal kidneys was noted either as a part of spectrum of syndrome or alone. CONCLUSIONS: In the era of exome sequencing, targeted gene sequencing is getting replaced and for better. However not all answers are direct, and sometimes the variant categorization is dependent on the acumen and agreement of all those involved in the process. It includes those involved the diagnostic as well those catering to the patients. It is very important to be updated on the relevance of multiple gene in causing similar phenotypes particularly in the prenatal context were coming up with a timely diagnosis is very important for any sort of intervention.

Molecular detection and association of 12.1 kb deletion within the high mobility AT-hook 2 gene in the Netherlands dwarf rabbit (Oryctolagus Cuniculus).

Rabbits are mainly bred for human consumption and medical research. However, it has been recently showed that several rabbit breeds are also kept as pets for human leisure. The Netherlands dwarf rabbit is currently in the immense interest of many Vietnamese customers due to its personality and miniature stature. However, 12.1 kb deletion from position 44,709,089 to 44,721,236 bp in the high mobility AT-hook 2 (HMGA2) gene on chromosome 4 was identified as the structural variant causing dwarfism and altered craniofacial development in this breed. It has been documented that HMGA2 plays an important role in regulating growth and individuals with genotype HMGA2 del/del are fatal several days after birth. Despite the economically high value of the Netherlands dwarf rabbit, there has been no study on the genetic survey of lethal alleles in this breed in Vietnam. The aim of this study is to develop a fast and reliable method to screen the frequency of lethal alleles of HMGA2 in the South of Vietnam. Rabbit saliva was collected, and DNA extraction was followed. Multiplex polymerase chain reaction (PCR) with three primers was optimized and performed to detect the presence of 12.1 kb deletion within the HMGA2 sequence. Our data showed that the 12.1 kb deletion in the Netherlands dwarf rabbit population was detected by our optimized multiplex PCR. In 100 rabbit animals, 34 and 16 individuals were homozygous wild type (+/+) and homozygous mutant (del/del), respectively, while 50 rabbits were heterozygous. The frequency of HMGA2 lethal allele carrier was 66% (66/100 individuals). Our results indicated that we successfully developed a fast, accurate multiplex PCR to detect carrier individuals. Verification of the genotypes was followed by sequencing. We recommend implementing our multiplex PCR procedure in genetic selection for carrier and homozygous wild-type animals in the mating scheme to prevent the lethality of the rabbit offspring. Additionally, awareness should be raised among rabbit breeders to monitor the genetic makeup of the Netherlands dwarf rabbit populations. However, due to the limitation of the sample size, more samples should be taken in future studies to obtain the genetic frequency of the HMGA2 lethal allele more accurately.

Investigating TNNC1 gene inheritance and clinical outcomes through a comprehensive familial study.

Hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM) have significant phenotypic overlap and a similar genetic background, both caused mainly by variants in sarcomeric genes. HCM is the most common cardiomyopathy, while RCM is a rare and often underdiagnosed heart condition, with a poor prognosis. This study focuses on a large family with four infants diagnosed with fatal RCM associated with biventricular hypertrophy. Affected infants were found to be homozygous for NM_003280.3(TNNC1):c.23C>T(p.Ala8Val) variant. Interestingly, this variant resulted in a low penetrance and mild form of hypertrophic cardiomyopathy (HCM) in relatives carrying a single copy of the variant. Overall, this study underscores the complex nature of genetic inheritance in cardiomyopathies and the wide range of clinical presentations they can exhibit. This emphasizes the vital role of genetic testing in providing essential insights crucial for diagnosis, prognosis, early intervention, and the development of potential treatment strategies.

Non-coding variants are a rare cause of recessive developmental disorders in trans with coding variants.

PURPOSE: Identifying pathogenic non-coding 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 non-coding 'second hits' in trans with these is unknown. METHODS: In 4,073 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 non-coding variants on the other haplotype in introns, untranslated regions (UTRs), promoters, and candidate enhancer regions. We clinically evaluated the top candidates for phenotypic fit, and performed functional testing where possible. RESULTS: We identified 3,761 rare heterozygous loss-of-function or ClinVar pathogenic variants in recessive DD-associated genes in 2,430 probands. For 1,366 (36.3%) of these, we identified at least one rare non-coding variant in trans. Bioinformatic filtering and clinical review, revealed seven to be a good clinical fit. After detailed characterisation, we identified likely diagnoses for three probands (in GAA, NPHP3, and PKHD1) and candidate diagnoses in a further three (PAH, LAMA2, IGHMBP2). CONCLUSION: We developed a systematic approach to uncover new diagnoses involving compound heterozygous coding/non-coding variants and conclude that this mechanism is likely to be a rare cause of DDs.