Biallelic variant in DACH1, encoding Dachshund Homolog 1, defines a novel candidate locus for recessive postaxial polydactyly type A.

Polydactyly or hexadactyly is characterized by an extra digit/toe with or without a bone. Currently, variants in ten genes have been implicated in the non-syndromic form of polydactyly. DNA from a single affected individual having bilateral postaxial polydactyly was subjected to whole exome sequencing (WES), followed by Sanger sequencing. Homology modeling was performed for the identified variant and advance microscopy imaging approaches were used to reveal the localization of the DACH1 protein at the base of primary cilia. A disease-causing biallelic missense variant (c.563G > A; p.Cys188Tyr; NM_080760.5) was identified in the DACH1 gene segregating perfectly within the family. Structural analysis using homology modeling of the DACH1 protein revealed secondary structure change that might result in loss of function or influence downstream interactions. Moreover, siRNA-mediated depletion of DACH1 showed a key role of DACH1 in ciliogenesis and cilia function. This study provides the first evidence of involvement of the DACH1 gene in digits development in humans and its role in primary cilia. This signifies the importance and yet unexplored role of DACH1.

Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and Other Coronaviruses: A Genome-wide Comparative Annotation and Analysis.

Novel strain of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) causes mild to severe respiratory illness. The early symptoms may be fever, dry cough, sour throat, and difficulty in breathing which may lead to death in severe cases. Compared to previous outbreaks like SARS-CoV and Middle East Respiratory Syndrome (MERS), SARS-CoV2 disease (COVID-19) outbreak has been much distressing due to its high rate of infection but low infection fatality rate (IFR) with 1.4% around the world. World Health Organization (WHO) has declared (COVID-19) a pandemic on March 11, 2020. In the month of January 2020, the whole genome of SARS-CoV2 was sequenced which made work easy for researchers to develop diagnostic kits and to carry out drug repurposing to effectively alleviate the pandemic situation in the world. Now, it is important to understand why this virus has high rate of infectivity or is there any factor involved at the genome level which actually facilitates this virus infection globally? In this study, we have extensively analyzed the whole genomes of different coronaviruses infecting humans and animals in different geographical locations around the world. The main aim of the study is to identify the similarity and the mutational adaptation of the coronaviruses from different host and geographical locations to the SARS-CoV2 and provide a better strategy to understand the mutational rate for specific target-based drug designing. This study is focused to every annotation in a comparative manner which includes SNPs, repeat analysis with the different categorization of the short-sequence repeats and long-sequence repeats, different UTR's, transcriptional factors, and the predicted matured peptides with the specific length and positions on the genomes. The extensive analysis on SNPs revealed that Wuhan SARS-CoV2 and Indian SARS-CoV2 are having only eight SNPs. Collectively, phylogenetic analysis, repeat analysis, and the polymorphism revealed the genomic conserveness within the SARS-CoV2 and few other coronaviruses with very less mutational chances and the huge distance and mutations from the few other species.

Biocomputational Prediction Approach Targeting FimH by Natural SGLT2 Inhibitors: A Possible Way to Overcome the Uropathogenic Effect of SGLT2 Inhibitor Drugs.

The Food and Drug Administration (FDA) approved a new class of anti-diabetic medication (a sodium-glucose co-transporter 2 (SGLT2) inhibitor) in 2013. However, SGLT2 inhibitor drugs are under evaluation due to their associative side effects, such as urinary tract and genital infection, urinary discomfort, diabetic ketosis, and kidney problems. Even clinicians have difficulty in recommending it to diabetic patients due to the increased probability of urinary tract infection. In our study, we selected natural SGLT2 inhibitors, namely acerogenin B, formononetin, (-)-kurarinone, (+)-pteryxin, and quinidine, to explore their potential against an emerging uropathogenic bacterial therapeutic target, i.e., FimH. FimH plays a critical role in the colonization of uropathogenic bacteria on the urinary tract surface. Thus, FimH antagonists show promising effects against uropathogenic bacterial strains via their targeting of FimH's adherence mechanism with less chance of resistance. The molecular docking results showed that, among natural SGLT2 inhibitors, formononetin, (+)-pteryxin, and quinidine have a strong interaction with FimH proteins, with binding energy (∆G) and inhibition constant (ki) values of -5.65 kcal/mol and 71.95 µM, -5.50 kcal/mol and 92.97 µM, and -5.70 kcal/mol and 66.40 µM, respectively. These interactions were better than those of the positive control heptyl α-d-mannopyranoside and far better than those of the SGLT2 inhibitor drug canagliflozin. Furthermore, a 50 ns molecular dynamics simulation was conducted to optimize the interaction, and the resulting complexes were found to be stable. Physicochemical property assessments predicted little toxicity and good drug-likeness properties for these three compounds. Therefore, formononetin, (+)-pteryxin, and quinidine can be proposed as promising SGLT2 inhibitors drugs, with add-on FimH inhibition potential that might reduce the probability of uropathogenic side effects.

Genetic investigations on causes of male infertility in Western Saudi Arabia.

In recent years, genetic studies have yielded great progress in elucidating causes of male infertility. This investigation aims to identify frequent genetic abnormalities, that is, sex chromosome aneuploidies and Y-chromosome microdeletions among infertile men in Western Saudi Arabia. From a population of infertile patients, 88 male patients with either azoospermia or severe oligozoospermia (sperm concentration <5 million/ml) were selected. In addition to a thorough clinical workup, karyotypes and Y-chromosomal microdeletions were investigated. Among those 88 infertile patients, we detected six patients with Klinefelter syndrome, two with 47 XYY syndrome and two with Y-chromosome microdeletions AZFb,c. While the prevalence of sex chromosome aneuploidies was in the range of globally investigated populations, the microdeletions appeared to be less frequent in Western Saudi Arabia compared to other regions of the world. All genetically abnormal cases showed sperm concentration <1 million/ml, and hence, this appears to be the threshold for warranting genetic investigations in Western Saudi Arabia. Since Klinefelter and 47 XYY syndromes were only discovered late in life, upon an infertility investigation, sex chromosome aneuploidies due to their many-fold comorbidities require earlier medical attention. A neonatal screening programme is suggested for detection of these aneuploidies in Saudi Arabia for the general health benefit of these patients.

Optimization of antibacterial activity of ethanolic extracts of Eucalyptus tereticornis and Nigella sativa: Response surface Methodology.

The screening of plants for medicinal purposes represents an effort to discover newer, safer, and possibly more effective drugs. Design of the present study was made aiming to the optimization of the antibacterial activity of ethanolic extracts of Eucalyptus tereticornis (leaves) and Nigella sativa (seeds) against bacteria belongings to both Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Escherichia coli) spectrum by using response surface methodology. 20 g powder of each E. tereticornis (leaf) and N. sativa (seeds) were mixed with 200ml of ethanol at room temperature, and then it was centrifuged at 4000 rpm for 10 min to separate the supernatants, and allowed to dry in order to obtain ethanol free extracts. A fresh bacterial culture of 100µl of test microorganism was inoculated onto media and spread homogeneously. The antimicrobial activity of ethanolic extracts showed that all the concentrations tested were effective against the test microorganisms. The diameters of zones of inhibition exhibited by S. aureus PCSIR-83 were in the range of 0-28mm, E. coli PCSIR-102 (0-28mm) and B. subtilis PCSIR-05 (15-26mm). The combination of N. sativa (15mg/µl) and E. tereticornis (20mg/µl) were found most effective at pH 9.0 and temperature 35°C. Our results clearly indicate that Gram positive bacteria showed more sensitivity than Gram-negative bacteria.

Assessment of IL-18 Serum Level and Its Promoter Polymorphisms in the Saudi Coronary Artery Disease (CAD) Patients.

The purpose of the current study was to find out the possible changes polymorphic site at the promoter region of IL-18 gene in Saudi CAD patients. We have also measured serum IL-18 level to find out, the likely association between its level and polymorphic site. The present study included total 197 subjects (98 confirmed CAD patients both men and women and 99 healthy control individuals). Serum concentration of IL-18 was measured by enzyme linked immuno-sorbent assay. For SNPs analysis, sanger method of DNA sequencing was followed. We observed variable numbers of SNPs at -137 C/G, -607 A/C, and -656 T/G promoter sites in our studied samples. However, the observed changes in the number of SNP hotspots were found to be non-significant compared with control. IL-18 level was found to be significantly (P < 0.001) elevated in CAD patients compared with control individuals. The highest rise of around 36% (P < 0.001) in IL-18 level was recorded in unstable angina (UA) patients. Moreover, the group belonging to UA and non-ST segment elevation myocardial infarction (NSTEMI) showed only 6% rise. On the basis of our result, inflammation seems to have a role in the pathogenesis of CAD but not leading to the significant changes at the genetic level. J. Cell. Biochem. 118: 1849-1854, 2017. © 2017 Wiley Periodicals, Inc.

Candida identification: a journey from conventional to molecular methods in medical mycology.

The incidence of Candida infections have increased substantially in recent years due to aggressive use of immunosuppressants among patients. Use of broad-spectrum antibiotics and intravascular catheters in the intensive care unit have also attributed with high risks of candidiasis among immunocompromised patients. Among Candida species, C. albicans accounts for the majority of superficial and systemic infections, usually associated with high morbidity and mortality often caused due to increase in antimicrobial resistance and restricted number of antifungal drugs. Therefore, early detection of candidemia and correct identification of Candida species are indispensable pre-requisites for appropriate therapeutic intervention. Since blood culture based methods lack sensitivity, and species-specific identification by conventional method is time-consuming and often leads to misdiagnosis within closely related species, hence, molecular methods may provide alternative for accurate and rapid identification of Candida species. Although, several molecular approaches have been developed for accurate identification of Candida species but the internal transcribed spacer 1 and 2 (ITS1 and ITS2) regions of the rRNA gene are being used extensively in a variety of formats. Of note, ITS sequencing and PCR-RFLP analysis of ITS region seems to be promising as a rapid, easy, and cost-effective method for identification of Candida species. Here, we review a number of existing techniques ranging from conventional to molecular approaches currently in use for the identification of Candida species. Further, advantages and limitations of these methods are also discussed with respect to their discriminatory power, reproducibility, and ease of performance.

The genetic cause of neurodevelopmental disorders in 30 consanguineous families.

Objective: This study aims to clinically and genetically assess 30 unrelated consanguineous Pakistani families from various ethnic backgrounds, all exhibiting features of neurodevelopmental disorders (NDDs). Methods: We conducted clinical, genetic, biochemical, and molecular analyses on 30 consanguineous families with NDDs enrolled from various regions of Pakistan. The likely molecular causes of primary microcephaly and NDDs were identified. Detailed clinical investigations and molecular diagnoses were performed using whole exome sequencing (WES) of the proband, followed by Sanger sequencing for validation and segregation in the available family members of the affected families. Results: WES identified likely disease-causing homozygous variants in 30 unrelated consanguineous families. Six families presented newly described variants in known NDD-related genes: ABAT (c.1439 T > G; p.Phe480Cys) [OMIM613163], SLC12A6 (c.2865_2865insT; p.Glu955Asnfs*5) [OMIM 218000], SHANK3 (c.1305-3_1,305-2delTT; p.Gln29-_Gly305del) [OMIM 606232], BCKDK (c.356_356insC; p.Gly119Alafs*24) [OMIM 614923], DDHD2 (c.2065G > T; p.Asp689Tyr) [OMIM 615033], ERCC2 (c.1255G > A; p.Glu419Lys) [OMIM 610756]. Additionally, 12 families had previously reported disease-causing variants associated with different types of NDDs: ATRX (c.109C > T; p.Arg37*) [OMIM 309580], GPR56 [ADGRG1] (c.1423C > T; p.Arg475*) [OMIM 606854], NAGLU (c.1694G > A; p.Arg565Gln) [OMIM 252920], DOLK (c.3G > A; p.Met1Ile) [OMIM 610768], GPT2 (c.815C > T; p.Ser272Leu) [OMIM 616281], DYNC1I2 (c.607 + 1G > A; p.?) [OMIM 618492], FBXL3 (c.885delT; p.Leu295Phefs25*) [OMIM 606220], LINGO1 (c.869G > A; p.Arg290His) [OMIM 618103], and ASPM (c.3978G > A; Trp1326*, c.9557C > G; p.Ser3186*, c.6994C > T; p.Arg2332*) [OMIM 608716]. All the identified variants showed segregation compatible with autosomal recessive inheritance. Conclusion: In the present study, we observed a high frequency of ASPM variants in the genetic analysis of 30 consanguineous families exhibiting features of NDDs, particularly those associated with autosomal recessive primary microcephaly. These findings contribute to studies on genotype-phenotype correlation, genetic counseling for families, and a deeper understanding of human brain function and development.

Cancer chemoprevention by polyphenols and their potential application as nanomedicine.

Today cancer is a leading cause of death among the developed countries. Its highly complex nature makes it difficult to understand as it entails multiple cellular physiological systems such as cell signaling and apoptosis. The biggest challenges faced by cancer chemoprevention/chemotherapy is maintaining drug circulation and avoiding multidrug resistance. Overall there is modest evidence regarding the protective effects of nutrients from supplements against a number of cancers. Numerous scientific literatures available advocate the use of polyphenols for chemoprevention. Some groups have also suggested use of combination of nutrients in cancer prevention. However, we have yet to obtain the desired results in the line of cancer chemotherapy research. Nanotechnology can play a pivotal role in cancer treatment and prevention. Moreover, nanoparticles can be modified in various ways to prolong circulation, enhance drug localization, increase drug efficacy, and potentially decrease the chances of multidrug resistance. In this communication, we will cover the use of various polyphenols and nutrients in cancer chemoprevention. The application of nanotechnology in this regard will also be included. In view of available reports on the potential of nanoparticles, we suggest their usage along with different combination of nutrients as cancer chemotherapeutic agents.

Molecular docking analysis of AGTR1 antagonists.

Cardiovascular diseases (CVDs) are the leading cause of death and morbidity globally. The renin-angiotensin system is an important regulatory system for maintaining cardiovascular and renal function. Therefore, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have emerged as first-line treatments for conditions such as hypertension and heart failure. Currently available synthetic medications used to treat various CVDs have been linked with various adverse effects. Therefore, this study focuses on targeting type-1 angiotensin II receptor (AGTR1) by natural compounds. The ZINC database natural compounds and standard AGTR1 inhibitors have been screened against the AGTR1 active site. The results showed that five compounds, namely ZINC85625504, ZINC62001623, ZINC70666587, ZINC06624086, and ZINC95486187, had similar binding energies to established AGTR1 inhibitors. These compounds were found to interact with crucial AGTR1 residues, indicating their potential as AGTR1 inhibitors. Moreover, the hit compounds demonstrated favorable drug-like characteristics and warrant further investigation for their potential use in managing CVD.

Loss-of-function variant in the LRR domain of SLITRK2 implicated in a neurodevelopmental disorder.

Background: Neurodevelopmental disorders are characterized by different combinations of intellectual disability (ID), communication and social skills deficits, and delays in achieving motor or language milestones. SLITRK2 is a postsynaptic cell-adhesion molecule that promotes neurite outgrowth and excitatory synapse development. Methods and Results: In the present study, we investigated a single patient segregating Neurodevelopmental disorder. SLITRK2 associated significant neuropsychological issues inherited in a rare X-linked fashion have recently been reported. Whole-exome sequencing and data analysis revealed a novel nonsense variant [c.789T>A; p.(Cys263*); NM_032539.5; NP_115928.1] in exon 5 of the SLITRK2 gene (MIM# 300561). Three-dimensional protein modeling revealed substantial changes in the mutated SLITRK2 protein, which might lead to nonsense-medicated decay. Conclusion: This study confirms the role of SLITRK2 in neuronal development and highlights the importance of including the SLITRK2 gene in the screening of individuals presenting neurodevelopmental disorders.

Insights from the molecular docking analysis of EGFR antagonists.

Overexpression of the epidermal growth factor receptor (EGFR) has been shown to be a critical factor in tumor development and cancer progression. Although established EGFR inhibitors have been effective in the treatment of cancer, they are associated with several side effects. As a result, there is an urgent need to develop novel EGFR inhibitors that can effectively target the receptor while causing no adverse side effects. Here, the bioactive compounds of Glycyrrhiza glabra and established EGFR inhibitors have been screened against the EGFR catalytic site. The compounds LTS0058805, LTS0114552, LTS0128805, LTS0174203, LTS0007447, and LTS0164690 exhibited binding energies to the EGFR that were comparable to those of established EGFR inhibitors. Further, these hit compounds were observed to interact with critical residues of the EGFR, suggesting their potential as inhibitors of the receptor. In addition, these hits possess good drug-like properties and merit further exploration for their potential application in cancer management.

Unveiling the multitargeted potency of Sodium Danshensu against cervical cancer: a multitargeted docking-based, structural fingerprinting and molecular dynamics simulation study.

Cervical Cancer (CC) is one of the most common types of cancer in women worldwide, with a significant number of deaths reported yearly. Despite the various treatment options available, the high mortality rate associated with CC highlights the need to develop new and effective therapeutic agents. In this study, we have screened the complete prepared FDA library against the Mitotic kinesin-like protein 1, Cyclin B1, DNA polymerase, and MCM10-ID using three glide-based molecular docking algorithms: HTVS, SP and XP to produce a robust calculation. All four proteins are crucial proteins that actively participate in CC development, and inhibiting them together can be a game-changer step for multitargeted drug designing. Our multitargeted screening identified Sodium (Na) Danshensu, a natural FDA-approved phenolic compound of caffeic acid derivatives isolated from Salvia miltiorrhiza. The docking score ranges from -5.892 to -13.103 Kcal/mol, and the screening study was evaluated with the pharmacokinetics and interaction fingerprinting to identify the pattern of interactions that revealed that the compound has bound to the best site it can be fitted to where maximum bonds were created to make the complex stable. The molecular dynamics simulations for 100 ns were then extended to validate the stability of the protein-ligand complexes. The results provide insight into the repurposing, and Na-danshensu exhibited strong binding affinity and stable complex formation with the target proteins, indicating its potential as a multitargeted drug against CC.Communicated by Ramaswamy H. Sarma.

Molecular docking analysis of KRAS inhibitors for cancer management.

The majority of human tumors are characterized by abnormal signaling caused by oncogenic RAS proteins. KRAS is a member of the RAS family and is currently one of the most thoroughly researched targets for cancer treatment due to its prevalence in a variety of deadly malignancies. Targeting the KRAS protein, which plays a crucial role in regulating cell growth, differentiation, and apoptosis, shows great potential as a strategy for fighting cancer. Herein, in silico screening of 530 natural compounds against KRAS protein was performed. The top-scoring hits, namely ZINC32502206, ZINC98363763, ZINC85645815, and ZINC98364259 displayed a robust affinity towards KRAS as evidenced by their respective binding affinity values of -10.50, -10.01, -9.80, and -9.70 kcal/mol, respectively which were notably higher than that of the control compound AMG 510 (-9.10 kcal/mol). Through virtual screening and visual inspection, it was observed that these hits effectively interacted with the essential residues located within the active site of KRAS. Based on the findings of this study, it can be inferred that these compounds may have the potential to be employed in the treatment of cancer by targeting KRAS.

Multitargeted inhibitory effect of Mitoxantrone 2HCl on cervical cancer cell cycle regulatory proteins: a multitargeted docking-based MM\GBSA and MD simulation study.

Cervical cancer remains a significant global health concern that starts in the cervix, the lower part of the uterus that connects to the vagina and is caused by the human papillomavirus (HPV), necessitating the development of effective multitargeted effective and resistance-proof therapies. In early-stage cervical cancer may not show any symptoms, however, as the cancer progresses, some people may experience- abnormal vaginal bleeding, watery or bloody vaginal discharge, pain in the pelvis or lower back, pain during sex, and frequent and painful urination. In this study, we screened the complete FDA-approved drug library using a multitargeted inhibitory approach against four cervical cancer proteins, namely mitotic arrest deficient -2, DNA polymerase epsilon B-subunit, benzimidazole-related -1, and threonine-protein kinase-1 which crucially plays its role for the in its development process. We employed the HTVS, SP and XP algorithms for efficient filtering and screening that helped to identify Mitoxantrone 2HCl against all of them with docking and MM\GBSA scores ranging from - 11.63 to - 7.802 kcal/mol and - 74.38 to - 47.73 kcal/mol, respectively. We also evaluated the interaction patterns of each complex and the pharmacokinetics properties that helped gain insight into interactions. Subsequently, we performed multiscale MD simulations for 100 ns to understand the dynamic behaviour and stability of the Mitoxantrone 2HCl -protein complexes that revealed the formation of stable drug-protein complexes and provided insights into the molecular interactions that contribute to Mitoxantrone's inhibitory effects on these proteins and can be a better drug for cervical cancer. However, experimental studies of these findings could pave the way for therapies to combat cervical cancer effectively.

Congenital disorder of glycosylation with defective fucosylation 2 (FCSK gene defect): The third report in the literature with a mild phenotype.

BACKGROUND: Congenital disorders of glycosylation (CDG) are a group of heterogeneous disorders caused by abnormal lipid or protein glycosylation. Variants in the FCSK gene have been reported to cause CDG. Defective FCSK-induced CDG (FCSK-CDG) has only been reported previously in three unrelated children. METHODS: In this study, we genetically and clinically examined a 3-year-old proband with resolved infantile spasms and normal development. Standard whole-exome sequencing (WES) and Sanger sequencing were performed to identify the functional impact of the variant. RESULTS: WES revealed a rare biallelic missense variant (c.3013G>C; p.Val1005Leu) in FCSK. RT-qPCR showed a significant depletion in FCSK gene expression in the affected individual. Western blotting revealed reduced FCSK expression at the protein level compared to that in the control. Furthermore, 3D protein modeling suggested changes in the secondary structure, which might affect the overall FCSK protein function. CONCLUSION: This study broadens the mutation and phenotypic spectrum of FCSK-associated developmental disorders.

Targeting Kaposi's sarcoma associated herpesvirus encoded protease (ORF17) by a lysophosphatidic acid molecule for treating KSHV associated diseases.

Kaposi's sarcoma associated herpesvirus (KSHV) is causative agent of Kaposi's sarcoma, Multicentric Castleman Disease and Pleural effusion lymphoma. KSHV-encoded ORF17 encodes a protease which cleaves -Ala-Ala-, -Ala-Ser- or -Ala-Thr-bonds. The protease plays an important role in assembly and maturation of new infective virions. In the present study, we investigated expression pattern of KSHV-encoded protease during physiologically allowed as well as chemically induced reactivation condition. The results showed a direct and proportionate relationship between ORF17 expression with reactivation time. We employed virtual screening on a large database of natural products to identify an inhibitor of ORF17 for its plausible targeting and restricting Kaposi's sarcoma associated herpesvirus assembly/maturation. A library of 307,814 compounds of biological origin (A total 481,799 structures) has been used as a screen library. 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-(1'-myo-inositol) was highly effective against ORF17 in in-vitro experiments. The screened compound was tested for the cytotoxic effect and potential for inhibiting Kaposi's sarcoma associated herpesvirus production upon induced reactivation by hypoxia, TPA and butyric acid. Treatment of reactivated KSHV-positive cells with 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-(1'-myo-inositol) resulted in significant reduction in the production of Kaposi's sarcoma associated herpesvirus. The study identified a lysophosphatidic acid molecule for alternate strategy to inhibit KSHV-encoded protease and target Kaposi's sarcoma associated herpesvirus associated malignancies.

Biallelic Variants in Seven Different Genes Associated with Clinically Suspected Bardet-Biedl Syndrome.

Bardet-Biedl syndrome (BBS) is a rare clinically and genetically heterogeneous autosomal recessive multi-systemic disorder with 22 known genes. The primary clinical and diagnostic features include six different hallmarks, such as rod-cone dystrophy, learning difficulties, renal abnormalities, male hypogonadism, post-axial polydactyly, and obesity. Here, we report nine consanguineous families and a non-consanguineous family with several affected individuals presenting typical clinical features of BBS. In the present study, 10 BBS Pakistani families were subjected to whole exome sequencing (WES), which revealed novel/recurrent gene variants, including a homozygous nonsense mutation (c.94C>T; p.Gln32Ter) in the IFT27 (NM_006860.5) gene in family A, a homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B, a homozygous nonsense variant (c.720C>A; p.Cys240Ter) in the WDPCP (NM_015910.7) in family C, a homozygous nonsense variant (c.505A>T; p.Lys169Ter) in the LZTFL1 (NM_020347.4) in family D, pathogenic homozygous 1 bp deletion (c.775delA; p.Thr259Leufs*21) in the MKKS/BBS5 (NM_170784.3) gene in family E, a pathogenic homozygous missense variant (c.1339G>A; p.Ala447Thr) in BBS1 (NM_024649.4) in families F and G, a pathogenic homozygous donor splice site variant (c.951+1G>A; p?) in BBS1 (NM_024649.4) in family H, a pathogenic bi-allelic nonsense variant in MKKS (NM_170784.3) (c.119C>G; p.Ser40*) in family I, and homozygous pathogenic frameshift variants (c.196delA; p.Arg66Glufs*12) in BBS5 (NM_152384.3) in family J. Our findings extend the mutation and phenotypic spectrum of four different types of ciliopathies causing BBS and also support the importance of these genes in the development of multi-systemic human genetic disorders.

Novel homozygous pathogenic mitochondrial DNAJC19 variant in a patient with dilated cardiomyopathy and global developmental delay.

BACKGROUND: Dilated cardiomyopathy with ataxia syndrome (DCMA) or 3-methylglutaconic aciduria type V is a rare global autosomal recessive mitochondrial syndrome that is clinically and genetically heterogeneous. It is characterized by early-onset dilated cardiomyopathy and increased urinary excretion of 3-methylglutaconic acid. As a result, some patients die due to cardiac failure, while others manifest with growth retardation, microcytic anemia, mild ataxia, and mild muscle weakness. DCMA is caused by variants in the DnaJ heat shock protein family (Hsp40) member C19 gene (DNAJC19), which plays an important role in mitochondrial protein import machinery in the inner mitochondrial membrane. METHODS: We describe a single affected family member who presented with cardiomyopathy, global developmental delay, chest infection, seizures, elevated excretion of 3-methylglutaconic acid, and 3-methylglutaric acid in the urine. RESULTS: Whole-exome sequencing followed by Sanger sequencing revealed a homozygous frameshift variant in the reading frame starting at codon 54 in exon 4 in the DNAJC19 gene (c.159del [Phe54Leufs*5]), which results in a stop codon four positions downstream. Quantitative gene expression analysis revealed that DNAJC19 mRNA expression in this patient was substantially reduced compared to the control. CONCLUSIONS: We present a novel variant in the DNAJC19 gene that causes rare autosomal recessive mitochondrial 3-methylglutaconic aciduria type V. By comparing the current case with previously reported ones, we conclude that the disease is extremely heterogeneous for reasons that are still unknown.