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Italian Journal of Pediatrics Jun 2024Townes-Brocks syndrome (TBS) is a rare genetic disorder characterized by imperforate anus, dysplastic ears, thumb malformations, and other abnormalities. Previous...
BACKGROUND
Townes-Brocks syndrome (TBS) is a rare genetic disorder characterized by imperforate anus, dysplastic ears, thumb malformations, and other abnormalities. Previous studies have revealed that mutations in the SALL1 gene can disrupt normal development, resulting in the characteristic features of Townes-Brocks syndrome. Spalt-like transcription factors (SALLs) are highly conserved proteins that play important roles in various cellular processes, including embryonic development, cell differentiation, and cell survival. Over 400 different variants or mutations have been reported in the SALL1 gene in individuals with TBS. Most of these variants lead to the formation of premature termination codons (PTCs), also known as nonsense mutations. The majority of these PTCs occur in a specific region of the SALL1 gene called the "hotspot region", which is particularly susceptible to mutation.
METHODS
In this study, we conducted whole-exome sequencing on a three-generation Chinese family with anorectal malformations.
RESULTS
We identified a novel heterozygous mutation (chr16:51175376:c.757 C > T p.Gln253*) in the SALL1 gene. Molecular analysis revealed a heterozygous C to T transition at nucleotide position 757 in exon 2 of the SALL1 (NM_002968) gene. This mutation is predicted to result in the substitution of the Gln253 codon with a premature stop codon (p.Gln253*). The glutamine-rich domain forms a long alpha helix, enabling the mutant protein to interact with the wild-type SALL1 protein. This interaction may result in steric hindrance effects on the wild-type SALL1 protein.
CONCLUSIONS
Our findings have expanded the mutation database of the SALL1 gene, which is significant for genetic counseling and clinical surveillance in the affected family. Furthermore, our study enhances the understanding of Townes-Brocks syndrome and has the potential to improve its diagnosis and treatment.
Topics: Humans; Transcription Factors; Abnormalities, Multiple; Anus, Imperforate; Female; Male; Pedigree; China; Mutation; Rare Diseases; Anorectal Malformations; Asian People; East Asian People; Hearing Loss, Sensorineural; Thumb
PubMed: 38915054
DOI: 10.1186/s13052-024-01691-0 -
BMC Medical Genomics Jun 2024Distal hereditary motor neuropathy (dHMN) is a heterogeneous group of hereditary diseases caused by the gradual degeneration of the lower motor neuron. More than 30...
BACKGROUND
Distal hereditary motor neuropathy (dHMN) is a heterogeneous group of hereditary diseases caused by the gradual degeneration of the lower motor neuron. More than 30 genes associated with dHMN have been reported, while 70-80% of those with the condition are still unable to receive a genetic diagnosis.
METHODS
A 26-year-old man experiencing gradual weakness in his lower limbs was referred to our hospital, and data on clinical features, laboratory tests, and electrophysiological tests were collected. To identify the disease-causing mutation, we conducted whole exome sequencing (WES) and then validated it through Sanger sequencing for the proband and his parents. Silico analysis was performed to predict the pathogenesis of the identified mutations. A literature review of all reported mutations of the related gene for the disease was performed.
RESULTS
The patient presented with dHMN phenotype harboring a novel homozygous variant c.361G > C (p.Ala121Pro) in SORD, inherited from his parents, respectively. A121 is a highly conserved site and the mutation was categorized as "likely pathogenic" according to the criteria and guidelines of the American College of Medical Genetics and Genomics (ACMG). A total of 13 published articles including 101 patients reported 18 SORD variants. Almost all described cases have the homozygous deletion variant c.757delG (p.A253Qfs*27) or compound heterozygous state of a combination of c.757delG (p.A253Qfs*27) with another variant. The variant c.361G > C (p.Ala121Pro) detected in our patient was the second homozygous variant in SORD-associated hereditary neuropathy.
CONCLUSION
One novel homozygous variant c.361G > C (p.Ala121Pro) in SORD was identified in a Chinese patient with dHMN phenotype, which expands the mutation spectrum of SORD-associated hereditary neuropathy and underscores the significance of screening for SORD variants in patients with undiagnosed hereditary neuropathy patients.
Topics: Humans; Male; Adult; Mutation; Exome Sequencing; Hereditary Sensory and Motor Neuropathy; Pedigree; Phenotype
PubMed: 38915017
DOI: 10.1186/s12920-024-01940-5 -
PeerJ 2024Polish Konik remains one of the most important horse breeds in Poland. The primitive, native horses with a stocky body and mouse-like coat color are protected by a...
Polish Konik remains one of the most important horse breeds in Poland. The primitive, native horses with a stocky body and mouse-like coat color are protected by a conservation program, while their Polish population consists of about 3,480 individuals, representing 16 dam and six sire lines. To define the population's genetic structure, mitochondrial DNA and Y chromosome sequence variables were identified. The mtDNA whole hypervariable region analysis was carried out using the Sanger sequencing method on 233 Polish Koniks belonging to all dam lines, while the Y chromosome analysis was performed with the competitive allele-specific PCR genotyping method on 36 horses belonging to all sire lines. The analysis of the mtDNA hypervariable region detected 47 SNPs, which assigned all tested horses to 43 haplotypes. Most dam lines presented more than one haplotype; however, five dam lines were represented by only one haplotype. The haplotypes were classified into six (A, B, E, J, G, R) recognized mtDNA haplogroups, with most horses belonging to haplogroup A, common among Asian horse populations. Y chromosome analysis allocated Polish Koniks in the Crown group, condensing all modern horse breeds, and divided them into three haplotypes clustering with coldblood breeds (28 horses), warmblood breeds (two horses), and Duelmener Pony (six horses). The clustering of all Wicek sire line stallions with Duelmener horses may suggest a historical relationship between the breeds. Additionally, both mtDNA and Y chromosome sequence variability results indicate crossbreeding before the studbooks closure or irregularities in the pedigrees occurred before the DNA testing introduction.
Topics: Animals; Horses; DNA, Mitochondrial; Poland; Y Chromosome; Haplotypes; Male; Polymorphism, Single Nucleotide; Female; Breeding
PubMed: 38912049
DOI: 10.7717/peerj.17549 -
Molecular Genetics and Metabolism... Sep 2024The detailed clinical phenotype of patients carrying the α-galactosidase gene () / () variant in Fabry disease (FD) has not been thoroughly documented in the...
BACKGROUND
The detailed clinical phenotype of patients carrying the α-galactosidase gene () / () variant in Fabry disease (FD) has not been thoroughly documented in the existing literature.
METHODS
This paper offers a meticulous overview of the clinical phenotype and relevant auxiliary examination results of nine confirmed FD patients with the gene variant from two families. Pedigree analysis was conducted on two male patients with the gene variant, followed by biochemical and genetic screening of all high-risk relatives. Subsequently, evaluation of multiple organ systems and comprehensive instrument assessment were performed on heterozygotes of the gene variant.
RESULTS
The study revealed that all patients exhibited varying degrees of cardiac involvement, with two demonstrating left ventricular wall thickness exceeding 15 mm on echocardiography, and the remaining six exceeding 11 mm. Impaired renal function was evident in all six patients with available blood test data, two of whom underwent kidney transplantation. Eight cases reported neuropathic pain, and five experienced varying degrees of stroke or transient ischemic attack (TIA).
CONCLUSION
This study indicates that the gene variant can induce premature organ damage, particularly affecting the heart, kidneys, and nervous system.
PubMed: 38911695
DOI: 10.1016/j.ymgmr.2024.101102 -
Dementia and Geriatric Cognitive... 2024Microglia exert a crucial role in homeostasis of white matter integrity, and several studies highlight the role of microglial dysfunctions in neurodegeneration. Primary...
INTRODUCTION
Microglia exert a crucial role in homeostasis of white matter integrity, and several studies highlight the role of microglial dysfunctions in neurodegeneration. Primary microgliopathy is a disorder where the pathogenic abnormality of the microglia causes white matter disorder and leads to a neuropsychiatric disease. Triggering receptor expressed on myeloid cells (), TYRO protein tyrosine kinase binding protein () and colony-stimulating factor 1 receptor () are genes implicated in primary microgliopathy. The clinical manifestations of primary microgliopathy are myriad ranging from neuropsychiatric syndrome, motor disability, gait dysfunction, ataxia, pure dementia, frontotemporal dementia (FTD), Alzheimer's dementia (AD), and so on. It becomes imperative to establish the diagnosis of microgliopathy masquerading as degenerative dementia, especially with promising therapies on horizon for the same. We aimed to describe a case series of subjects with dementia harbouring novel genes of primary microgliopathy, along with their clinical, neuropsychological, cognitive profile and radiological patterns.
METHODS
The prospective study was conducted in a university referral hospital in South India, as a part of an ongoing clinico-genetic research on dementia subjects, and was approved by the Institutional Ethics Committee. All patients underwent detailed assessment including sociodemographic profile, clinical and cognitive assessment, pedigree analysis and comprehensive neurological examination. Subjects consenting for blood sampling underwent genetic testing by whole-exome sequencing (WES).
RESULTS
A total of 100 patients with dementia underwent genetic analysis using WES and three pathogenic variants, one each of , , and and two variants of uncertain significance in were identified as cause of primary microgliopathy. and presented as frontotemporal syndrome whereas CSF1R presented as frontotemporal syndrome and as AD.
CONCLUSION
WES has widened the spectrum of underlying neuropathology of degenerative dementias, and diagnosing primary microglial dysfunction with emerging therapeutic options is of paramount importance. The cases of primary microgliopathy due to novel mutations in , , and with the phenotype of degenerative dementia are being first time reported from Indian cohort. Our study enriches the spectrum of genetic variants implicated in degenerative dementia and provides the basis for exploring complex molecular mechanisms like microglial dysfunction, as underlying cause for neurodegeneration.
PubMed: 38910897
DOI: 10.1159/000538145 -
Journal of Dairy Science Jun 2024This study explores how the metafounder (MF) concept enhances genetic evaluations in dairy cattle populations using single-step genomic best linear unbiased prediction...
This study explores how the metafounder (MF) concept enhances genetic evaluations in dairy cattle populations using single-step genomic best linear unbiased prediction (ssGBLUP). By improving the consideration of relationships among founder populations, MF ensures accurate alignment of pedigree and genomic relationships. The research aims to propose a method for grouping MF based on genotypic information, assess different approaches for estimating the gamma matrix, and compare unknown parent groups (UPG) and MF methodologies across various scenarios, including those with low and high pedigree completeness based on a simulated dairy cattle population. In the scenario where unknown ancestors are rare, the impact of UPG or MF on breeding values is minimal but MF still performs slightly better compared with UPG. The scenario with lower genotyping rates and more unknown parents shows significant differences in evaluations with and without UPG and also compared with MF. The study shows that ssGBLUP evaluations where UPG are considered via Quaas-Pollak-transformation in the pedigree-based and genomic relationship matrix (UPG_fullQP) results in double counting and subsequently in a pronounced bias and overdispersion. Another focus is on the estimation of the gamma matrix, emphasizing the importance of crossbred genotypes for accuracy. Challenges emerge in classifying animals into subpopulations and further into MF or UPG, but the method used in this study, which is based on genotypes, results in predictions which are comparable to those obtained using the true subpopulations for the assignment. Estimated validation results using the linear regression method confirm the superior performance of MF evaluations, although differences compared with true validations are smaller. Notably, UPG_fullQP's extreme bias is less evident in routine validation statistics.
PubMed: 38908687
DOI: 10.3168/jds.2024-24891 -
Scientific Reports Jun 2024Hereditary spastic paraplegias are a diverse group of degenerative disorders that are clinically categorized as isolated; with involvement of lower limb spasticity, or...
Hereditary spastic paraplegias are a diverse group of degenerative disorders that are clinically categorized as isolated; with involvement of lower limb spasticity, or symptomatic, where spastic paraplegia is complicated by further neurological features. We sought to identify the underlying genetic causes of these disorders in the participating patients. Three consanguineous families with multiple affected members were identified by visiting special schools in the Punjab Province. DNA was extracted from blood samples of the participants. Exome sequencing was performed for selected patients from the three families, and the data were filtered to identify rare homozygous variants. ExomeDepth was used for the delineation of the copy number variants. All patients had varying degrees of intellectual disabilities, poor speech development, spasticity, a wide-based gait or an inability to walk and hypertonia. In family RDHR07, a homozygous deletion involving multiple exons and introns of SPG11 (NC000015.9:g.44894055_449028del) was found and correlated with the phenotype of the patients who had spasticity and other complex movement disorders, but not those who exhibited ataxic or indeterminate symptoms as well. In families ANMD03 and RDFA06, a nonsense variant, c.985C > T;(p.Arg329Ter) in DDHD2 and a frameshift insertion‒deletion variant of AP4B1, c.965-967delACTinsC;p.(Tyr322SerfsTer14), were identified which were homozygous in the patients while the obligate carriers in the respective pedigrees were heterozygous. All variants were ultra-rare with none, or very few carriers identified in the public databases. The three loss of function variants are likely to cause nonsense-mediated decay of the respective transcripts. Our research adds to the genetic variability associated with the SPG11 and AP4B1 variants and emphasizes the genetic heterogeneity of hereditary spastic paraplegia.
Topics: Humans; Male; Female; DNA Copy Number Variations; Pedigree; Spastic Paraplegia, Hereditary; Exons; Child; Adolescent; Adult; Exome Sequencing; Child, Preschool; Adaptor Protein Complex 4; Consanguinity; Homozygote; Phenotype; Young Adult; Proteins
PubMed: 38906889
DOI: 10.1038/s41598-024-64922-8 -
Frontiers in Genetics 2024Several mutations in the gene have been identified as a causative link to VWS. In this investigation, whole-exome sequencing (WES) and Sanger sequencing of a...
Several mutations in the gene have been identified as a causative link to VWS. In this investigation, whole-exome sequencing (WES) and Sanger sequencing of a three-generation pedigree with an autosomal-dominant inheritance pattern affected by VWS identified a unique stop-gain mutation-c.748C>T:p.R250X-in the gene that co-segregated exclusively with the disease phenotype. Immunofluorescence analysis revealed that the -p.R250X mutation predominantly shifted its localization from the nucleus to the cytoplasm. WES and protein interaction analyses were conducted to understand this mutation's role in the pathogenesis of VWS. Using LC-MS/MS, we found that this mutation led to a reduction in the binding of IRF6 to histone modification-associated proteins (NAA10, SNRPN, NAP1L1). Furthermore, RNA-seq results show that the mutation resulted in a downregulation of TGFβ2-AS1 expression. The findings highlight the mutation's influence on and its subsequent effects on the phosphorylation of SMAD2/3, which are critical in maxillofacial development, particularly the palate. These insights contribute to a deeper understanding of VWS's molecular underpinnings and might inform future therapeutic strategies.
PubMed: 38903762
DOI: 10.3389/fgene.2024.1397410 -
Genetics, Selection, Evolution : GSE Jun 2024Previous research showed that deviations in longitudinal data are heritable and can be used as a proxy for pigs' general resilience. However, only a few studies...
BACKGROUND
Previous research showed that deviations in longitudinal data are heritable and can be used as a proxy for pigs' general resilience. However, only a few studies investigated the relationship between these resilience traits and other traits related to resilience and welfare. Therefore, this study investigated the relationship between resilience traits derived from deviations in longitudinal data and traits related to animal resilience, health and welfare, such as tail and ear biting wounds, lameness and mortality.
RESULTS
In our experiment, 1919 finishing pigs with known pedigree (133 Piétrain sires and 266 crossbred dams) were weighed every 2 weeks and scored for physical abnormalities, such as lameness and ear and tail biting wounds (17,066 records). Resilience was assessed via deviations in body weight, deviations in weighing order and deviations in observed activity during weighing. The association between these resilience traits and physical abnormality traits was investigated and genetic parameters were estimated. Deviations in body weight had moderate heritability estimates (h = 25.2 to 36.3%), whereas deviations in weighing order (h = 4.2%) and deviations in activity during weighing (h = 12.0%) had low heritability estimates. Moreover, deviations in body weight were positively associated and genetically correlated with tail biting wounds (r = 0.22 to 0.30), lameness (r = 0.15 to 0.31) and mortality (r = 0.19 to 0.33). These results indicate that events of tail biting, lameness and mortality are associated with deviations in pigs' body weight evolution. This relationship was not found for deviations in weighing order and activity during weighing. Furthermore, individual body weight deviations were positively correlated with uniformity at the pen level, providing evidence that breeding for these resilience traits might increase both pigs' resilience and within-family uniformity.
CONCLUSIONS
In summary, our findings show that breeding for resilience traits based on deviations in longitudinal weight data can decrease pigs' tail biting wounds, lameness and mortality while improving uniformity at the pen level. These findings are valuable for pig breeders, as they offer evidence that these resilience traits are an indication of animals' general health, welfare and resilience. Moreover, these results will stimulate the quantification of resilience via longitudinal body weights in other species.
Topics: Animals; Lameness, Animal; Swine; Tail; Bites and Stings; Female; Male; Body Weight; Breeding; Quantitative Trait, Heritable; Phenotype; Swine Diseases
PubMed: 38902596
DOI: 10.1186/s12711-024-00919-1 -
European Journal of Medical Genetics Jun 2024This paper reports the discovery of a m.C1494T pedigree in the east of England made during a search for matrilineal relations of King Richard III. The mitochondrial DNA...
This paper reports the discovery of a m.C1494T pedigree in the east of England made during a search for matrilineal relations of King Richard III. The mitochondrial DNA variant m.C1494T has been associated with aminoglycoside-induced deafness. This variant is very uncommon. although pedigrees with this variant have previously been found in China and Spain. The members of the newly identified pedigree all belong to the mitochondrial haplogroup J1c2c3, which is also the haplogroup of King Richard III. The presence of a few people in the USA from the same haplogroup has previously been noted, and it is now known that one of the people can show his descent from a couple who lived in Nottinghamshire, England, in the late 1700's. The mitochondrial DNA sequence of this man, at present living in the USA, and of his 4th cousin, twice removed, living in Lincoln, England, has shown they belong to haplogroup J1c2c3 and both have the variant m.C1494T; thereby, allowing the production of a multi-generational pedigree originating in the east of England. Fortunately, deafness has not been found in any living member of this large pedigree. It was also noted that the link to the family of King Richard III has not been firmly defined; however the circumstantial evidence is strong as many of his family members lived in this part of England.
PubMed: 38897372
DOI: 10.1016/j.ejmg.2024.104957