scholarly journals Identification of a compound heterozygote in LYST gene: a case report on Chediak-Higashi syndrome

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Yinsen Song ◽  
Zhengping Dong ◽  
Shuying Luo ◽  
Junmei Yang ◽  
Yuebing Lu ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Genetic Diseases ◽  
Amplicon Sequencing ◽  
Bone Marrow Examination ◽  
Pathogenic Mutation ◽  
Pedigree Analysis ◽  
Compound Heterozygote ◽  
Loss Of Function ◽  
Causative Gene ◽  
Chediak Higashi Syndrome

Abstract Background Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disease caused by loss of function of the lysosomal trafficking regulator protein. The causative gene LYST/CHS1 was cloned and identified in 1996, which showed significant homology to other species such as bovine and mouse. To date, 74 pathogenic or likely pathogenic mutations had been reported. Case presentation Here we describe a compound heterozygote in LYST gene, which was identified in a 4-year-old female patient. The patient showed skin hypopigmentation, sensitivity to light, mild splenomegaly and reduction of platelets in clinical examination. Giant intracytoplasmic inclusions were observed in the bone marrow examination, suggesting the diagnosis of CHS. Amplicon sequencing was performed to detect pathogenic mutation in LYST gene. The result was confirmed by two-generation pedigree analysis base on sanger sequencing. Conclusion A compound heterozygote in LYST gene, consisting of a missense mutation c.5719A > G and an intron mutation c.4863-4G > A, was identified from the patient by using amplicon sequencing. The missense mutation is reported for the first time. Two-generation pedigree analysis showed these two mutations were inherited from the patient’s parents, respectively. Our result demonstrated that amplicon sequencing has great potential for accelerating and improving the diagnosis of rare genetic diseases.

DMC1 mutation that causes human non-obstructive azoospermia and premature ovarian insufficiency identified by whole-exome sequencing

2018 ◽  
Vol 55 (3) ◽  
pp. 198-204 ◽  
Author(s):  
Wen-Bin He ◽  
Chao-Feng Tu ◽  
Qiang Liu ◽  
Lan-Lan Meng ◽  
Shi-Min Yuan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
Male Patient ◽  
Histological Analysis ◽  
Pedigree Analysis ◽  
Obstructive Azoospermia ◽  
Ovarian Insufficiency ◽  
Causative Gene ◽  
Whole Exome

BackgroundThe genetic causes of the majority of male and female infertility caused by human non-obstructive azoospermia (NOA) and premature ovarian insufficiency (POI) with meiotic arrest are unknown.ObjectiveTo identify the genetic cause of NOA and POI in two affected members from a consanguineous Chinese family.MethodsWe performed whole-exome sequencing of DNA from both affected patients. The identified candidate causative gene was further verified by Sanger sequencing for pedigree analysis in this family. In silico analysis was performed to functionally characterise the mutation, and histological analysis was performed using the biopsied testicle sample from the male patient with NOA.ResultsWe identified a novel homozygous missense mutation (NM_007068.3: c.106G>A, p.Asp36Asn) in DMC1, which cosegregated with NOA and POI phenotypes in this family. The identified missense mutation resulted in the substitution of a conserved aspartic residue with asparaginate in the modified H3TH motif of DMC1. This substitution results in protein misfolding. Histological analysis demonstrated a lack of spermatozoa in the male patient’s seminiferous tubules. Immunohistochemistry using a testis biopsy sample from the male patient showed that spermatogenesis was blocked at the zygotene stage during meiotic prophase I.ConclusionsTo the best of our knowledge, this is the first report identifying DMC1 as the causative gene for human NOA and POI. Furthermore, our pedigree analysis shows an autosomal recessive mode of inheritance for NOA and POI caused by DMC1 in this family.

scholarly journals A missense mutation of the Dhh gene is associated with male pseudohermaphroditic rats showing impaired Leydig cell development

Reproduction ◽  
2011 ◽  
Vol 141 (2) ◽  
pp. 217-225 ◽  
Author(s):  
Yasuhiro Kawai ◽  
Junko Noguchi ◽  
Kouyou Akiyama ◽  
Yuriko Takeno ◽  
Yasuhiro Fujiwara ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Recessive Gene ◽  
Testicular Development ◽  
Specific Marker ◽  
Androgen Deficiency ◽  
Loss Of Function ◽  
Causative Gene ◽  
Mutant Rat

Development of the male gonads is a complex process with interaction of various cells in the gonads including germ, Sertoli, Leydig, and myoid cells. TF is a mutant rat strain showing male pseudohermaphroditism, with agenesis of Leydig cells and androgen deficiency controlled by an autosomal single recessive gene (mp). The mp locus was mapped on the distal region of rat chromosome 7 by linkage analysis, but the gene responsible for the mp mutation has not been identified. In this study, we performed fine linkage mapping and sequence analysis to determine the causative gene of the mp mutation, and performed an immunohistochemical study using a Leydig cell-specific marker to investigate detailed phenotypes of the mutant rats during the testicular development. As a result, we found a missense mutation of the gene encoding Desert hedgehog (Dhh) in the mutant rat, which could result in loss of function of the DHH signaling pathway. Histochemical examination revealed remarkably reduced number of fetal Leydig cells and lack of typical spindle-shaped adult Leydig cell in the mp/mp rats. These phenotypes resembled those of the Dhh-null mice. Additionally, testosterone levels were significantly lower in the mp/mp fetus, indicating androgen deficiency during embryonic development. These results indicate that the mutation of the Dhh gene may be responsible for the pseudohermaphrodite phenotypes of the mutant rat, and that the Dhh gene is probably essential for the development of Leydig cells.

scholarly journals Homozygous RRM2 Variant Might Lead to Early Embryo Developmental Arrest: A Case Report

2020 ◽  
Author(s):  
Xiong Wang ◽  
Zhen-teng Liu ◽  
Yan-wei Sha ◽  
Xiao-yan Liu ◽  
Hai-long Wang ◽  
...  
Keyword(s):  
Autosomal Recessive Inheritance ◽  
Pathogenic Mutation ◽  
Pedigree Analysis ◽  
Early Embryo ◽  
Causative Gene ◽  
Developmental Arrest ◽  
Cycle Arrest ◽  
Online Databases ◽  
Maternal Effect Gene

Abstract Background: Early embryonic developmental stagnation is one of the reasons that affect the outcome of in vitro fertilization-embryo transfer, leading to the depletion of available embryos or failure after transplantation. It has been shown that defects in the ribonucleotide-reductase lead to cell cycle arrest, developmental delay, and high mutation rates.Case presentation: Two female patients, who were siblings from an inbreeding family, suffered primary infertility of unknown causes and early embryonic developmental arrest during IVF treatment. A total of 39 oocytes were obtained from the patients in collectively 5 IVF/ICSI cycles, of which 37 were mature eggs, only 2 transplantable embryos were formed, and no pregnancy was achieved. Whole genome sequencing and Sanger sequencing were adopted to identify and confirm variations that might cause early embryo developmental stagnation in this family. We identified a homozygous variant c.262C>T:p.His88Tyr in ribonucleotide-diphosphate reductase subunit M2 (RRM2) in both patients and their parents each carried a heterozygous allele. Pedigree analysis showed an autosomal recessive inheritance pattern. Function of this variant was predicted by online databases, which indicated it to be a potential pathogenic mutation. Conclusions: We identified RRM2 as a potential causative gene for early embryonic developmental stagnation. It was also suggested that RRM2 might be a maternal effect gene.

scholarly journals Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset

2021 ◽  
Vol 22 (7) ◽  
pp. 3786
Author(s):  
Andreas Brodehl ◽  
Alexey Meshkov ◽  
Roman Myasnikov ◽  
Anna Kiseleva ◽  
Olga Kulikova ◽  
...  
Keyword(s):  
Medical History ◽  
Splice Site Mutation ◽  
Pathogenic Mutation ◽  
Large Deletion ◽  
Loss Of Function ◽  
Arrhythmogenic Cardiomyopathy ◽  
Site Mutation ◽  
Snp Arrays ◽  
Number Of Patients ◽  
History Of

About 50% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2–c.378+1G>T) in the first patient and a nonsense mutation (DSG2–p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.

scholarly journals Biochemical Characterization of the GBA2 c.1780G>C Missense Mutation in Lymphoblastoid Cells from Patients with Spastic Ataxia

2018 ◽  
Vol 19 (10) ◽  
pp. 3099 ◽  
Author(s):  
Anna Malekkou ◽  
Maura Samarani ◽  
Anthi Drousiotou ◽  
Christina Votsi ◽  
Sandro Sonnino ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Autosomal Recessive ◽  
Biochemical Characterization ◽  
Fold Increase ◽  
Loss Of Function ◽  
Spastic Paraplegia ◽  
Spastic Ataxia ◽  
Autosomal Recessive Cerebellar Ataxia ◽  
Compensatory Effect

The GBA2 gene encodes the non-lysosomal glucosylceramidase (NLGase), an enzyme that catalyzes the conversion of glucosylceramide (GlcCer) to ceramide and glucose. Mutations in GBA2 have been associated with the development of neurological disorders such as autosomal recessive cerebellar ataxia, hereditary spastic paraplegia, and Marinesco-Sjogren-Like Syndrome. Our group has previously identified the GBA2 c.1780G>C [p.Asp594His] missense mutation, in a Cypriot consanguineous family with spastic ataxia. In this study, we carried out a biochemical characterization of lymphoblastoid cell lines (LCLs) derived from three patients of this family. We found that the mutation strongly reduce NLGase activity both intracellularly and at the plasma membrane level. Additionally, we observed a two-fold increase of GlcCer content in LCLs derived from patients compared to controls, with the C16 lipid being the most abundant GlcCer species. Moreover, we showed that there is an apparent compensatory effect between NLGase and the lysosomal glucosylceramidase (GCase), since we found that the activity of GCase was three-fold higher in LCLs derived from patients compared to controls. We conclude that the c.1780G>C mutation results in NLGase loss of function with abolishment of the enzymatic activity and accumulation of GlcCer accompanied by a compensatory increase in GCase.

scholarly journals The Landscape of Human STR Variation

2014 ◽  
Author(s):  
Thomas F. Willems ◽  
Melissa Gymrek ◽  
Gareth Highnam ◽  
The Genomes Project ◽  
David Mittelman ◽  
...  
Keyword(s):  
Tandem Repeats ◽  
Phase 1 ◽  
Genetic Diseases ◽  
Point Mutations ◽  
Graphical Interface ◽  
Loss Of Function ◽  
Human Reference Genome ◽  
Str Loci ◽  
Classical Point ◽  
Short Tandem

Short Tandem Repeats are among the most polymorphic loci in the human genome. These loci play a role in the etiology of a range of genetic diseases and have been frequently utilized in forensics, population genetics, and genetic genealogy. Despite this plethora of applications, little is known about the variation of most STRs in the human population. Here, we report the largest-scale analysis of human STR variation to date. We collected information for nearly 700,000 STR loci across over 1,000 individuals in phase 1 of the 1000 Genomes Project. This process nearly saturated common STR variations. After employing a series of quality controls, we utilize this call set to analyze determinants of STR variation, assess the human reference genome?s representation of STR alleles, find STR loci with common loss-of-function alleles, and obtain initial estimates of the linkage disequilibrium between STRs and common SNPs. Overall, these analyses further elucidate the scale of genetic variation beyond classical point mutations. The resource is publicly available at http://strcat.teamerlich.org/ both in raw format and via a graphical interface. 

scholarly journals Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Fang Wang ◽  
Shujia Huang ◽  
Rongsui Gao ◽  
Yuwen Zhou ◽  
Changxiang Lai ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Phenotypic Variability ◽  
Missense Variant ◽  
Pedigree Analysis ◽  
Chinese Patients ◽  
Genetic Contribution ◽  
Loss Of Function ◽  
Genomic Study ◽  
Significant Gene ◽  
Host Genetic

Abstract The COVID-19 pandemic has accounted for millions of infections and hundreds of thousand deaths worldwide in a short-time period. The patients demonstrate a great diversity in clinical and laboratory manifestations and disease severity. Nonetheless, little is known about the host genetic contribution to the observed interindividual phenotypic variability. Here, we report the first host genetic study in the Chinese population by deeply sequencing and analyzing 332 COVID-19 patients categorized by varying levels of severity from the Shenzhen Third People’s Hospital. Upon a total of 22.2 million genetic variants, we conducted both single-variant and gene-based association tests among five severity groups including asymptomatic, mild, moderate, severe, and critical ill patients after the correction of potential confounding factors. Pedigree analysis suggested a potential monogenic effect of loss of function variants in GOLGA3 and DPP7 for critically ill and asymptomatic disease demonstration. Genome-wide association study suggests the most significant gene locus associated with severity were located in TMEM189–UBE2V1 that involved in the IL-1 signaling pathway. The p.Val197Met missense variant that affects the stability of the TMPRSS2 protein displays a decreasing allele frequency among the severe patients compared to the mild and the general population. We identified that the HLA-A*11:01, B*51:01, and C*14:02 alleles significantly predispose the worst outcome of the patients. This initial genomic study of Chinese patients provides genetic insights into the phenotypic difference among the COVID-19 patient groups and highlighted genes and variants that may help guide targeted efforts in containing the outbreak. Limitations and advantages of the study were also reviewed to guide future international efforts on elucidating the genetic architecture of host–pathogen interaction for COVID-19 and other infectious and complex diseases.

A de novo missense mutation inSLC12A5found in a compound heterozygote patient with epilepsy of infancy with migrating focal seizures

2017 ◽  
Vol 92 (6) ◽  
pp. 654-658 ◽  
Author(s):  
T. Saito ◽  
A. Ishii ◽  
K. Sugai ◽  
M. Sasaki ◽  
S. Hirose
Keyword(s):  
Missense Mutation ◽  
De Novo ◽  
Compound Heterozygote ◽  
Focal Seizures

Frameshift mutation of Timm8a1 gene in mouse leads to an abnormal mitochondrial structure in the brain, correlating with hearing and memory impairment

2020 ◽  
pp. jmedgenet-2020-106925
Author(s):  
Pingping Song ◽  
Yuqing Guan ◽  
Xia Chen ◽  
Chaochen Wu ◽  
An Qiao ◽  
...  
Keyword(s):  
Memory Impairment ◽  
Manganese Superoxide Dismutase ◽  
Frameshift Mutation ◽  
Intermembrane Space ◽  
Loss Of Function ◽  
Electron Microscopic ◽  
Causative Gene ◽  
Western Blot Assay ◽  
Mitochondrial Structure ◽  
The Brain

BackgroundDeafness-dystonia-optic neuronopathy (DDON) syndrome is a progressive X-linked recessive disorder characterised by deafness, dystonia, ataxia and reduced visual acuity. The causative gene deafness/dystonia protein 1 (DDP1)/translocase of the inner membrane 8A (TIMM8A) encodes a mitochondrial intermembrane space chaperon. The molecular mechanism of DDON remains unclear, and detailed information on animal models has not been reported yet.Methods and resultsWe characterized a family with DDON syndrome, in which the affected members carried a novel hemizygous variation in the DDP1 gene (NM_004085.3, c.82C>T, p.Q28X). We then generated a mouse line with the hemizygous mutation (p.I23fs49X) in the Timm8a1 gene using the clustered regularly interspaced short palindromic repeats /Cas9 technology. The deficient DDP1 protein was confirmed by western blot assay. Electron microscopic analysis of brain samples from the mutant mice indicated abnormal mitochondrial structure in several brain areas. However, Timm8a1I23fs49X/y mutation did not affect the import of mitochondria inner member protein Tim23 and outer member protein Tom40 as well as the biogenesis of the proteins in the mitochondrial oxidative phosphorylation system and the manganese superoxide dismutase (MnSOD / SOD-2). The male mice with Timm8a1I23fs49X/y mutant exhibited less weight gain, hearing impairment and cognitive deficit.ConclusionOur study suggests that frameshift mutation of the Timm8a1 gene in mice leads to an abnormal mitochondrial structure in the brain, correlating with hearing and memory impairment. Taken together, we have successfully generated a mouse model bearing loss-of-function mutation in Timm8a1.

scholarly journals Bi-allelic SHOC1 loss-of-function mutations cause meiotic arrest and non-obstructive azoospermia

2020 ◽  
pp. jmedgenet-2020-107042
Author(s):  
Chencheng Yao ◽  
Chao Yang ◽  
Liangyu Zhao ◽  
Peng Li ◽  
Ruhui Tian ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Periodic Acid ◽  
Compound Heterozygous ◽  
Obstructive Azoospermia ◽  
Autosomal Recessive Mode ◽  
Loss Of Function ◽  
Meiotic Arrest ◽  
Causative Gene ◽  
Periodic Acid Schiff ◽  
Mode Of Inheritance

BackgroundThe genetic causes of human idiopathic non-obstructive azoospermia (NOA) with meiotic arrest remain unclear.MethodsTwo Chinese families with infertility participated in the study. In family 1, two brothers were affected by idiopathic NOA. In family 2, the proband was diagnosed with idiopathic NOA, and his elder sister suffered from infertility. Whole-exome sequencing (WES) was conducted in the two patients in family 1, the proband in family 2 and 362 additional sporadic patients with idiopathic NOA. Sanger sequencing was used to verify the WES results. Periodic acid–Schiff (PAS), immunohistochemistry (IHC) and meiotic chromosomal spread analyses were carried out to evaluate the stage of spermatogenesis arrested in the affected cases.ResultsWe identified compound heterozygous loss of function (LoF) variants of SHOC1 (c.C1582T:p.R528X and c.231_232del:p.L78Sfs*9, respectively) in both affected cases with NOA from family 1. In family 2, homozygous LoF variant in SHOC1 (c.1194delA:p.L400Cfs*7) was identified in the siblings with infertility. PAS, IHC and meiotic chromosomal spread analyses demonstrated that the spermatogenesis was arrested at zygotene stage in the three patients with NOA. Consistent with the autosomal recessive mode of inheritance, all of these SHOC1 variants were inherited from heterozygous parental carriers. Intriguingly, WES of 362 sporadic NOA cases revealed one additional NOA case with a bi-allelic SHOC1 LoF variant (c.1464delT:p.D489Tfs*13).ConclusionTo the best of our knowledge, this is the first report identifying SHOC1 as the causative gene for human NOA. Furthermore, our study showed an autosomal recessive mode of inheritance in the NOA caused by SHOC1 deficiency.

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