Year 2019, Volume 2 - Issue 1

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Background: Human serpin gene SERPINH1 encodes for a non-inhibitory serpin shock protein 47kDa (HSP47) a client-specific chaperone, which is a hallmark in the collagen biosynthesis. Till today, there is no comprehensive study on the protein network for human HSP47. Thus the current study aimed at studying the pathway and expression patterns observed in collagen-specific chaperone, HSP47 in relation to cancer. Methodology: The study used online database STRING 10 (website: http://version10a.string-db.org (7)) in finding putative protein interaction partners of human HSP47. Also, database HMMER3 (www.hmmer.org/) with Pfam 32.0 (Sept 2018) dataset was used in identifying Pfam protein domains from proteins interacting with HSP47. The db DEPC 3.0, was used for evaluation of expression patterns of HSP47 in different cancer. Further three online resources namely, human protein atlas (HPA, https://www.proteinatlas.org/), genotype-tissue expression (GTEx https://gtexportal.org) and FANTOM5 project (http://fantom.gsc.riken.jp/5/) was used to examine HSP47 expression in normal human tissues. Results: Upon constructing protein interactive map of human HSP47, the study found that a set of molecular chaperones as interaction partners of HSP47, which included two copies each of cAMP response element binding (CREB) binding proteins, HSP27, HSP40, HSP70, HSP90, ubiquitin proteins and one copy each of cartilage associated protein (CRTAP), HSPH1, HSBP1, FK506-binding protein 4 (FKBP4), kruppel-like factor (KLF13), peptidyl-prolyl isomerase PIPB and Prolyl 4-hydroxylase beta subunit (P4HB). Conclusion: The study found a cocktail of different chaperones interacting with HSP47, originated at different time points from prokaryotes to eukaryotes. Overall, the study was successful in finding HSP47 expression patterns among several normal tissues using three different publicly available datasets. It also assessed the expression pattern of HSP47 in human cancer types. These findings will encourage further studies focusing on the role of HSP47 in human diseases.

Background: Couples who are at risk for having an infant with a serious genetic disorder can benefit from pre-implantation genetic diagnosis (PGD), but many couples still opt for the riskier pre-natal diagnosis (PND). Although couples make this decision together, the male and the female in the couple may have different attitudes toward choosing PGD vs. PND. The objective of this study was to determine if men and women in the same couple with at least one child with a genetic disorder will have significantly different attitudes toward choosing PGD vs. PND. Methodology: In this cross-sectional clinical study, couples with at least one child with a genetic disease attending the King Faisal Specialist Hospital Research Center, Genetic Counseling Clinic (KFSH-RC, GCC), Riyadh, Saudi Arabia were asked to complete an anonymous survey about their attitudes towards PGD vs. PND. The responses were compared between men and women in couples. The study was conducted during May 2017. Results: A total of 38 couples provided complete surveys. In terms of preference for PGD vs. PND, there were no significant differences in aggregate between men and women (p > 0.05). Over half the couples agreed (were concordant) on all statements about PGD vs. PND. An almost equal number of couples with members who disagreed (were discordant) had women preferring PND vs. men preferring PND compared to PGD. Conclusion: This study showed that members of couples sampled were generally in agreement about their preference for PGD vs. PND. Among discordant couples, there was no preference among women for PGD vs. PND. Studies like this are important to help clinicians understand intra-couple dynamics in genetic counseling.

Background: Primary Hyperoxaluria Type 1 (PH1) is an inborn error of metabolism caused by mutations in the AGXT gene, which encodes for the hepatocyte-specific enzyme alanine: glyoxylate aminotransferase (AGT). AGT catalyzes the conversion of glyoxylate to glycine in the peroxisome and prevents the build-up of oxalate which occurs in PH1. This causes nephrocalcinosis, systemic oxalosis, and end-stage renal disease. Liver transplant is currently the only curative treatment available. Although a mouse model has previously been generated, the severity of the reported disease phenotype varies, and a better understanding of the genotype-phenotype relationship in both the mouse model and human disease is needed. Methods: We developed an Agxt-/- mouse model using CRISPR/Cas9-mediated gene editing. We performed a natural history study and ethylene glycol (EG) challenge to evaluate the phenotype of this mouse. Results: Agxt-/- mice had elevated plasma glycolate, urine glycolate, and urine oxalate levels compared to Agxt+/+ mice. A small subset of Agxt-/- mice developed minimal nephrocalcinosis (1/8 at 12 weeks, 1/8 at 26 weeks, 0/8 at 39 weeks, and 3/7 at 52 weeks of age). When challenged with 0.7% or 1.2% EG in drinking water for 3 weeks, 2/10 Agxt-/- mice developed nephrocalcinosis. Agxt2mRNA and protein expression were unchanged between Agxt-/- and Agxt+/+ mice. Hydroxy acid oxidase 1(Hao1) messenger ribonucleic acid (mRNA) levels were unchanged, but the corresponding glycolate oxidase protein was increased in Agxt-/- mice. Conclusion: We have created an Agxt-/- mouse model which resembles much of the clinical phenotype of PH1 patients and will be a useful tool in developing novel therapies for this devastating disease.

Glutaric aciduria type I (GA1) is an inherited metabolic disorder in which excessive levels of the amino acids lysine, hydroxylysine, and tryptophan accumulate in the body as a result of defective glutaryl-CoA dehydrogenase (GCDH) enzyme activity. Excessive metabolites are toxic that can cause damage to the brain, particularly due to the occurrence of basal ganglia and intellectual disability. Missense, splicing, and other deletion mutations in GCDH gene lead to the deficiency of the enzyme activity and are known to cause GA1. The severity of GA1 along with its neurological manifestations and clinical outcome is dependent upon the age at onset and therefore, early definitive diagnosis of GA1 becomes essential. GA1 occurs in approximately 1 of every 30,000-40,000 individuals worldwide that may reach up to 1 in 300 newborn babies in the Amish and Canadian communities. Owing to very high consanguinity rates in Saudi Arabia, it is presumed to be much more common in the Kingdom and is one of the initial disorders that were included in the country's neonatal screening program. In the current study, we have reviewed clinical manifestations, diagnosis, updated management, and mutation spectrum in GA1 with an example of one of our patients with GA1, and highlighted the importance of multipara-metric strategy in the early diagnosis and management of the disease.

Mitochondrial disorders are genetic conditions those faces great challenge in the accurate diagnoses due to extensive clinical heterogeneity associated with it. Mitochondria are the only cellular organelles containing their own genome and their functions are governed by both the nuclear and maternally inherited mitochondrial genomes, thus mitochondrial disease could follow all possible modes of inheritance adding to the complexity of diagnosis. Even though the prevalence of the mitochondrial disease has been studied in various parts of the world, the data regarding their prevalence in the Middle East population remains very limited. However, novel mitochondrial disease genes have been identified within the highly consanguineous Arab Middle East population, with the help of novel genetic technologies including the high throughput next-generation sequencing, leading to the identification of important founder mutations underlying several mitochondrial disorders. Furthermore, novel variants in mitochondrial disease genes help in expanding the spectrum of clinical phenotypes studied. The enrichment of reported phenotypes could enhance targeted gene panels leading to a rapid and precise genetic diagnosis facilitating genetic counseling. The aim of this review is to highlight the impact of next-generation sequencing on mitochondrial disease diagnosis in the Middle East population, particularly in identifying novel candidate genes and founder mutations.

Background: Bainbridge-Ropers syndrome (BRPS) is characterized by failure to thrive, global developmental delay, feeding problems, hypotonia, profound speech delays, and intellectual disability and dysmorphic features. It is an autosomal dominant condition caused by heterozygous mutations in the ASXL3 gene (OMIM #615115) on chromosome 18q12. As per the literature available, only 39 cases including the current patient were reported with BRPS across the globe. Case presentation: A 4-year-old girl with confirmed BRPS. She had the characteristic features of the disease including psychomotor delay, hypotonia, profound speech impairment, neonatal feeding difficulties, postnatal, and dysmorphic features. The array CGH and whole exome sequencing were negative, but the whole genome sequencing detected a novel heterozygous de novo insertion in the ASXL3 gene c.3592_3593insGAT; p.Leu1198X. Conclusion: With the advent of whole exome/genome sequencing we would expect to diagnose more cases of BRPS from different ethnic populations. Further clinical and functional studies are needed to delineate the long-term course of the disease and to elaborate on the exact role of the ASXL3 gene in brain development.

Background With recent advances in array comparative genomic hybridization (aCGH) methods, several, previously unrecognized pathogenic copy number variants (CNVs) have been recognized. Intrachromosomal triplications are rare and have been reported in a few genomic regions. In this report, we describe an infant with complex chromosomal rearrangement involving the long arm of chromosome 11 with concomitant triplication, duplication, and segmental area of absence of heterozygosity (AOH). Case Presentation: We report an infant who was presented with dysmorphic features, severe failure to thrive, developmental delay, dysgenesis of the corpus callosum, and intestinal obstruction. The aCGHshowed 19,930 megabases (Mb) triplication at 11q13.3q14.3, 346 kilobases(Kb) duplication at 11q14.3 and an area of AOH at 11q14.3-qter. Conclusion The occurrence of triplication along with AOH (most likely as a result of segmental uniparental isodisomy) is a rare, complex genomic rearrangement. It is suggested that these complex genomic rearrangements coupled with segmental uniparental isodisomy arise as a result of one-ended DNA break repair coupled with microhomology-mediated break-induced replication (MMBIR).

Background: Childhood nephrolithiasis cases reported worldwide has been increasing over the last decade. The majority of cases reported are related to calcium oxalate formation which results in impairment of glycine transport in the renal tubule leading to hyperglycinuria and impaired urinary oxalate excretion with resultant nephrolithiasis. Case presentation: A 4-year-old boy was presented with oxalate nephrolithiasis and hyperglycinuria. Molecular testing confirmed a c.448G>A p. (Val150Met) mutation of heterozygous status in SLC36A2 gene. Conclusion: The likelihood of cases being reported with renal hyperglycinuria along with oxalate nephrolithiasis is very rare. The present study reports a patient presented with oxalate nephrolithiasis, hyperglycinuria and a molecular confirmation for a heterozygous c.448G>A p. (Val150Met) mutation in SLC36A2 gene.

Background: A very few diseases are reported caused due to cerebellar hypoplasia and neuronal migration defects like pachygyria. Cerebellar Ataxia, mental retardation, and Dysequilibrium Syndrome 1 (DES) (OMIM # 224050) are one among such group of diseases. DES is caused due to a homozygous mutation in the VLDLR gene involved majorly in neuronal migration. Case Presentation: Two members (siblings) from a Turkish family presented with neuromotor developmental delay, moderate learning disability, delayed psychosocial development and strabismus complaints. Whole exome sequencing (WES) was performed as consanguinity existed between the parents and specific pre-diagnosis could not provide a satisfactory conclusion for the patients. WES revealed a homozygote novel mutation in the VLDLR gene. Conclusion: Evaluation of WES data resembled a process of finding a needle in a haystack; therefore, the present study recommended clinical information and anamnesis to be very important in understanding and interpreting the WES result.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a hyper-inflammatory condition resulting from altered crosstalk between innate and adaptive immune responses. Familial HLH is caused by mutations in several genes whereas the acquired form is associated with infections, rheumatic diseases, malignancies, and inherited metabolic disorders. Case Presentation: We report an infant boy who developed HLH and the potential involvement of mitochondrial DNA in pathogenicity. This patient was with evidence of mitochondrial disease based on neonatal-onset lactic acidosis, elevated lactate in cerebrospinal fluid, a significant lactate peak on magnetic resonance spectroscopy, and generalized reduction of multiple respiratory chain enzyme complex activities. In addition, full mitochondrial genome sequencing only revealed the identification of the homoplasmic m.4325A>G mutation. Subsequently, he presented with a febrile illness complicated by HLH. Conclusion: Elevated levels of lactic acidosis and mitochondrial dysfunction strengthen the involvement of mitochondria in causing secondary HLH in our patient.

Background: Familial hemiplegic migraine (FHM) is a rare disorder presented commonly with coma, hyperthermia, and headache. FHM is usually associated with fully reversible motor weakness as a specific symptom of aura. Seizure and fever are the secondary features observed. All the affected individuals were subjected to several laboratory tests. Case presentation: Three sisters diagnosed with type 2 familial hemiplegic migraines presenting features such as coma and hyperthermia. The brain (MRI) revealed focal subtle cortical swelling, Electroencephalography (EEG) showed unilateral slowing, while no signs of infectious disease were observed. Molecular and genetic tests using whole exome sequencing (WES) identified a novel heterozygous mutation (c.2450T>A p.Ile817Asn) in the exon 18 of the ATP1A2 gene (NM_000702.3). The variant segregated with the disease phenotype within the family. Conclusion: The current study report for the first time, a Saudi family with migraine coma having a novel heterozygous AT1A2 mutation.