Musharraf Jelani
@icp.edu.pk
Associate Professor, Centre for Omic Sciences
Islamia College, Peshawar
EDUCATION
PhD in Human Skin Disorders, MPhil in Human Ectodermal Dysplasias, Master in Biochemistry Molecular Biology.
RESEARCH INTERESTS
Human Genetics, Rare Mendelian Disorders, Exome Analysis, Bioinformatics.
Scopus Publications
Scopus Publications
Elbatool G. Elalem, Musharraf Jelani, Alaa Khedr, Aftab Ahmad, Tareef Y. Alaama, Mohamed Nabeel Alaama, Huda M. Al-Kreathy, and Zoheir A. Damanhouri
Public Library of Science (PLoS)
Backgrounds Inter-individual variability in response to statin was mainly due to genetic differences. This study aimed to investigate the association of CYP3A4*22 (rs35599367), CYP3A5*3 (rs776746) single nucleotide polymorphism (SNP) with response to simvastatin in hypercholesterolemia patients conducted at King Abdulaziz University hospital (KAUH) in Jeddah, Saudi Arabia. Patients and methods A total of 274 participants were registered in the current study. Hypercholesterolemic patients taking simvastatin 20 mg (n = 148) and control subjects (n = 126) were tested for rs35599367 and rs776746 genotypes using Custom Taqman ® Assay Probes. Response to simvastatin in these patients was assessed by determination of low density lipoprotein (LDL-C), total cholesterol (TC) and by measuring statin plasma levels using Liquid Chromatography-Mass Spectrometry (LC-MS). Results None of the participants carried a homozygous CYP3A4*22 mutant genotype, while 12 (4.4%) individuals had a heterozygous genotype and 262 (95.6%) had a wild homozygous genotype. The CYP3A5*3 allele was detected in the homozygous mutant form in 16 (5.8%) individuals, while 74 (27.0%) individuals carried the heterozygous genotype and 184 (67.2%) carried the wildtype homozygous genotype. Of the patient group, 15 (11%) were classified as intermediate metabolizers (IMs) and 133 (89%) as extensive metabolizers (EMs). Plasma simvastatin concentrations for the combined CYP3A4/5 genotypes were significantly (P<0.05) higher in the IMs group than in the EMs group. TC and plasma LDL-C levels were also significantly (P<0.05) higher in IMs than in EMs. Conclusion The present study showed associations between CYP3A4*22 (rs35599367) and CYP3A5*3 (rs776746) SNP combination genotypes with response to statins in hypercholesterolemia. Patients who had either a mutant homozygous allele for CYP3A5*3 or mutant homozygous and heterozygous alleles for CYP3A4*22 showed increased response to lower TC and LDL-C levels.
Atta Ullah Khan, Ibrar Khan, Muhammad Ismail Khan, Muhammad Latif, Muhammad Imran Siddiqui, Shafi Ullah Khan, Thet Thet Htar, Ghazala Wahid, Ikram Ullah, Fehmida Bibi,et al.
Wiley
Mitochondrial protein synthesis requires three elongation factors including EF-Tu (TUFM; OMIM 602389), EF-Ts (TSFM; OMIM 604723), and EF-G1 (GFM1; OMIM 606639). Pathogenic variants in any of these three members result in defective mitochondrial translation which can impart an oxidative phosphorylation (OXPHOS) deficiency. In this study, we investigated a consanguineous Pakhtun Pakistani family. There were four affected siblings at the time of this study and one affected girl had died in infancy. The index patient had severe intellectual disability, global developmental delay, dystonia, no speech development, feeding difficulties, and nystagmus. MRI brain presented thinning of corpus callosum and polymicrogyria. Whole exome sequencing revealed a novel compound heterozygous variant in GFM1 located on chromosome 3q25.32. Sanger sequencing confirmed recessive segregation of the maternal (NM_001308164.1:c.409G > A; p.Val137Met) and paternal (NM_001308164.1:c.1880G > A; p.Arg627Gln) variants in all the four affected siblings. These variants are classified as "likely-pathogenic" according to the recommendation of ACMG/AMP guideline. GFM1 alterations mostly lead to severe phenotypes and the patients may die in early neonatal life; however, four of the affected siblings had survived till the ages of 10-17 years, without developing any life-threatening conditions. Mostly, in cousin marriages, the pathogenic variants are identical-by-descent, and affected siblings born to such parents are homozygous. Three homozygous variants were shortlisted in the analysis of the WES data, but Sanger sequencing did not confirm their segregation with the disease phenotype. This is the first report from Pakistan expanding pathogenicity of GFM1 gene.
S. Pastore, Tahir Muhammad, R. Harripaul, R. Lau, Muhammad Tariq Masood Khan, Muhammad Ismail Khan, O. Islam, Changsoo Kang, M. Ayub, M. Jelani and John B. Vincent
In a multi-branch family from Pakistan, individuals presenting with palmoplantar keratoderma segregate in autosomal dominant fashion, and individuals with intellectual disability (ID) segregate in apparent autosomal recessive fashion. Initial attempts to identify the ID locus using homozygosity-by-descent (HBD) mapping were unsuccessful. However, following an assumption of locus heterogeneity, a reiterative HBD approach in concert with whole exome sequencing (WES) was employed. We identified a known disease-linked mutation in the polymicrogyria gene, ADGRG1, in two affected members. In the remaining two (living) affected members, HBD mapping cross-referenced with WES data identified a single biallelic frameshifting variant in the gene encoding retinol dehydrogenase 14 (RDH14). Transcription data indicate that RDH14 is expressed in brain, but not in retina. Magnetic resonance imaging for the individuals with this RDH14 mutation show no signs of polymicrogyria, however cerebellar atrophy was a notable feature. RDH14 in HEK293 cells localized mainly in the nucleoplasm. Co-immunoprecipitation studies confirmed binding to the proton-activated chloride channel 1 (PACC1/TMEM206), which is greatly diminished by the mutation. Our studies suggest RDH14 as a candidate for autosomal recessive ID and cerebellar atrophy, implicating either disrupted retinoic acid signaling, or, through PACC1, disrupted chloride ion homeostasis in the brain as a putative disease mechanism.
Fozia Fozia, Rubina Nazli, Nousheen Bibi, Sher Alam Khan, Noor Muhammad, Nafila Shakeeb, Saadullah Khan, Musharraf Jelani, and Naveed Wasif
Frontiers Media SA
Epidermolysis bullosa (EB) is a genetic skin disorder that shows heterogeneous clinical fragility. The patients develop skin blisters congenitally or in the early years of life at the dermo-epithelial junctions, including erosions, hyperkeratosis over the palms and soles. The other associated features are hypotrichosis on the scalp, absent or dystrophic nails, and dental anomalies. Molecular diagnosis through whole-exome sequencing (WES) has become one of the successful tool in clinical setups. In this study, three Pakhtun families from the Khyber Pakhtunkhwa province of Pakistan were ascertained. WES analysis of a proband in each family revealed two novel variants (COL17A1: NM_000494.4: c.4041T&gt;G: p.Y1347* and PLEC: NM_201380.3: c.1283_1285delGCT: p.L426del) and one previously known COL17A1: NM_000494.4:c.3067C&gt;T: p.Q1023*) variant in homozygous forms. Sanger sequencing of the identified variants confirmed that the heterozygous genotypes of the obligate carriers. The identified variants have not only increased the mutation spectrum of the COL17A1 and PLEC but also confirms their vital role in the morphogenesis of skin and its associated appendages. WES can be used as a first-line diagnostic tool in genetic testing and counselling families from Khyber Pakhtunkhwa, Pakistan.
Obaid Ur Rahman, Jeena Kim, Caroline Mahon, Musharraf Jelani, and Changsoo Kang
Springer Science and Business Media LLC
BACKGROUND
Amyloidosis cutis dyschromica (ACD) is a rare variant of cutaneous amyloidosis. This disorder often clusters in families, and it has been suggested that genetic factors might be involved in its development.
OBJECTIVE
To identify the genetic causes of ACD, we recruited a consanguineous Pakistani family with multiple cases of ACD that display a recessive mode of inheritance.
METHODS
We performed whole-exome sequencing of samples from 7 members of this family, followed by bioinformatic and in silico analyses to identify the causative variant. For the replication study, we recruited a British family with Pakistani ancestry, and sequenced all exons of glycoprotein non-metastatic melanoma protein b (GPNMB) to identify mutations. We also investigated effects of the mutations on the stability of the GPNMB protein using the I-TASSER three-dimensional modeling tool.
RESULTS
We found a novel homozygous mutation, p.Gly363Val (c.1088 G>T), in GPNMB in all affected cases. In a replication study, another homozygous missense mutation in GPNMB, pIle174Met (c.522 C>G), was carried by the affected son. The two mutations were not observed in our in-house data set comprising 217 healthy Pakistani individuals or in The Genome Aggregation Database. Our structural modeling of GPNMB suggested that p.Gly363Val enhanced its stability, whereas p.Ile174Met caused instability.
CONCLUSIONS
This study reports two novel missense mutations in two Pakistani families that cause ACD. The mutations appear to influence GPNMB stability, as revealed by protein modeling.
Muhammad Tariq, Muhammad Latif, Memona Inam, Amin Jan, Nousheen Bibi, Hussein Sheikh Ali Mohamoud, Isse Ali, Habib Ahmad, Aziz Khan, Jamal Nasir,et al.
Elsevier BV
Muhammad Ismail Khan, Muhammad Latif, Maria Saif, Hilal Ahmad, Atta Ullah Khan, Muhammad Imran Naseer, Hafiz Muhammad Jafar Hussain, and Musharraf Jelani
Wiley
BACKGROUND
Joubert syndrome (JBTS) is a heterogenous disorder characterized by intellectual disability, developmental delays, molar tooth sign in brain imaging, hypotonia, ocular motor apraxia, and overlapping features of ciliopathies. There are 36 clinical subtypes of JBTS with an equal number of genes known so far for this phenotype.
METHODS
Whole exome sequencing (WES) and Sanger sequencing were performed for the molecular diagnosis of a Pakhtun family affected with Joubert syndrome type 9 (JBTS9).
RESULTS
A novel homozygous missense variant (c.4417C>G; Pro1473Ala) in exon 34 was identified in coiled-coil and C2 domains-containing protein 2A (CC2D2A; NM_001080522) gene. The variant co-segregated in autosomal recessive fashion within the family and was not found in 200 ethnically matched unaffected individuals. In-silico analyses supported the pathogenic effect of the altered CC2D2A protein.
CONCLUSION
To the best of our knowledge, this is the first report of CC2D2A alteration co-segragating with JBTS9 phenotype in a Pakhtun family from Pakistan. Our findings broaden the pathogenic spectrum of JBTS9, adding a novel variant to CC2D2A variations' pool. WES analysis is a successful molecular diagnostic tool for the rare genetic disorders specially in those populations where cousin marriages are more frequent. Efficient and accurate genetic testing and counselling of the affected families are helpful in patients' management and to reduce the disease burden in future generations.
Hizbullah, Sagheer Ahmed, Mah Noor Mumtaz, Zaira Zulfiqar, Sheikh Amir Hamza, Sami Siraj, Musharraf Jelani, Imran Imran, and Asifullah Khan
Elsevier BV
The genetic polymorphism of cytochrome P450 (CYPs)drug-metabolizing enzymes are well studied in human populations for drug safety and efficacy. CYP2C9 is a highly polymorphic CYP enzyme that oxidizing the indigenous compounds and xenobiotics. The present study was pursued to evaluate the genetic variation across the CYP2C9 gene among major groups of the Pakistani population. The CYP2C9 genomic region holding important warfarin drug-metabolizing SNPs was sequenced from 159 individuals belong from five major ethnic groups of Pakistani population. The population genetic analyses of the high-quality sequences data was performed using Arlequin v3.5, DnaSP v6.12 and Network 5 resources. The data analyses unveiled that genetic variance among samples mainly arose from population-scale differentiation among these ethnic groups with global Fst of 0.78, P-value < 0.0001. The highest pairwise population genetic variation observed between Saraiki and Baloch groups based on different statistical tests. Whereas, uniform genetic composition across CYP2C9 loci was inferred among Punjabi, Pathan and Sindhi groups with minimal genetic differentiation. Several SNPs, including the previously reported warfarin associated variants, i.e. rs2860905, rs1799853 (CYP2C9*2) and rs72558189 (CYP2C9*14) were detected in these population groups with diverse frequencies. Also, a novel intronic SNP, i.e. not available in dbSNP and Ensemble databases, was identified for a Sindhi individual sample. This novel SNP predicted to influence the CYP2C9 alternative transcript splicing. The pharmacogeneticsassessment of the CYP2C9 genetic variations identified in current study may important to test against the warfarin efficacy for different ethnicity of Pakistani population.
Ghazanfar Ali, Naheed Bashir Awan, Sadia, Abdul Waheed Khawaja, Jia Nee Foo, Chiea Chuen Khor, Chu‐Hua Chang, Elaine GuoYan Chew, Farhat Rafique Kiani, and Musharraf Jelani
Wiley
Congenital atrichia (CA) is a rare form of irreversible alopecia with an autosomal recessive mode of inheritance. This form of hair loss is mainly associated with mutations in the human hairless (HR) gene located at chromosome 8p21.3. An additional unique feature atrichia with papular lesions (APL) comprises keratin‐filled cysts known as papules. The present study aimed to uncover the underlying genetic causes of APL in two consanguineous Kashmiri families.
Nuha Alrayes, Abdul Aziz, Farman Ullah, Muhammad Ishfaq, Musharraf Jelani, and Abdul Wali
Wiley
Syndactyly is a clinical feature of split‐hand foot malformation (SHFM), ectodermal‐dysplasia‐syndactyly (EDSS1) and Cenani–Lenz syndactyly syndromes (CLSS). In EDSS1, only cutaneous syndactyly is observed, with sparse hair, abnormal nails and dentition. In SHFM, bony syndactyly may vary from hypoplasia of one phalanx to aplasia of central digits, extending to complete fusion of all fingers and toes in CLSS. Several genes have been assigned to these syndromes. Performing a single step molecular diagnostics becomes a challenge when a phenotype has overlaps with several syndromes or when some of the clinical features are not fully expressed in patients.
Sadia, Jia Nee Foo, Chiea Chuen Khor, Musharraf Jelani, and Ghazanfar Ali
Wiley
Hypohidrotic ectodermal dysplasia (HED) is a rare congenital disorder arising from the abnormal development of ectoderm derived structures, including skin, hair, nails, teeth and glands. These patients have sparse hair on the whole body, including the scalp, as well as hypoplastic teeth. They have no resistance to heat as a result of abnormal sweat glands. In total, four genes, namely ectodysplasin A (EDA), ectodysplasin A receptor (EDAR), EDAR‐associated death domain protein (EDARADD) and Wnt family member 10A (WNT10A), are known to be involved in the etiology of HED.
Musharraf Jelani, Hannah C. Dooley, Andrea Gubas, Hussein Sheikh Ali Mohamoud, Muhammad Tariq Masood Khan, Zahir Ali, Changsoo Kang, Fazal Rahim, Amin Jan, Nirmal Vadgama,et al.
Oxford University Press (OUP)
Defects in autophagy are implicated in a growing number of diseases. Jelani et al. identify a mutation in WIPI2, a major autophagy gene, associated with a multisystemic global developmental disorder. Functional studies in cell lines derived from patients reveal significant reductions in the classic hallmarks of autophagy.
Sami Raja Alallasi, Amal A. Kokandi, Babajan Banagnapali, Noor Ahmad Shaik, Bandar Ali Al-Shehri, Nuha Mohammad Alrayes, Jumana Yousuf Al-Aama, and Musharraf Jelani
Frontiers Media SA
Background: Lamellar ichthyosis is an autosomal recessive type of rare skin disorders characterized with defective epidermis leading hyperkeratosis with brownish-gray scales over the body. These patients are born as collodion babies and may also exhibit additional features like erythema, ectropion, and eclabium. This disease is mainly caused by homozygous and compound heterozygous alterations in transglutaminase 1 encoding gene (TGM1), which is located on 14q12. Case presentation: This study reports the genetic analysis of a 4-year Saudi girl presenting lamellar ichthyosis. She was the first child of unrelated parents. The family had no previous history of the disease phenotype. She was born as a collodion baby without any prenatal complications. At the time of this study she had developed rough scaly skin on her legs, arms and trunk regions with thick palms and soles. Whole exome sequencing (WES) followed by Sanger sequence validation identified a novel compound heterozygous variant in TGM1 gene. The paternal variant was a missense transition (c.1141G>A; p.Ala381Thr) present at exon 7, while maternal variant (c.758-1G>C) was present at the intron4-exon5 boundary. To the best of our knowledge these variants had not been reported before in TGM1 gene. Conclusion: In isolated and inbred populations, homozygous variants are identified more frequently; however, our results suggest that compound heterozygous variants should also be considered especially when the marriages are not consanguineous.
Hussein Sheikh Mohamoud, Saleem Ahmed, Musharraf Jelani, Nuha Alrayes, Kay Childs, Nirmal Vadgama, Mona Mohammad Almramhi, Jumana Yousuf Al-Aama, Steve Goodbourn, and Jamal Nasir
Springer Science and Business Media LLC
Childhood onset clinical syndromes involving intellectual disability and dysmorphic features, such as polydactyly, suggest common developmental pathways link seemingly unrelated phenotypes. We identified a consanguineous family of Saudi origin with varying complex features including intellectual disability, speech delay, facial dysmorphism and polydactyly. Combining, microarray based comparative genomic hybridisation (CGH) to identify regions of homozygosity, with exome sequencing, led to the identification of homozygous mutations in five candidate genes (RSPH6A, ANKK1, AMOTL1, ALKBH8, TRAPPC6A), all of which appear to be pathogenic as predicted by Proven, SIFT and PolyPhen2 and segregate perfectly with the disease phenotype. We therefore looked for differences in expression levels of each protein in HEK293 cells, expressing either the wild-type or mutant full-length cDNA construct. Unexpectedly, wild-type TRAPPC6A appeared to be unstable, but addition of the proteasome inhibitor MG132 stabilised its expression. Mutations have previously been reported in several members of the TRAPP complex of proteins, including TRAPPC2, TRAPPC9 and TRAPPC11, resulting in disorders involving skeletal abnormalities, intellectual disability, speech impairment and developmental delay. TRAPPC6A joins a growing list of proteins belonging to the TRAPP complex, implicated in clinical syndromes with neurodevelopmental abnormalities.
Soheir Adam, Maha Badawi, Galila Zaher, Bandar Alshehri, Ahmed Basaeed, Musharraf Jelani, and Abdullah Kashqari
Medknow
Two variants for APOL1; the gastrointestinal (G1) variant (S342G and 1384M substitutions) and the G2 variant (N388 and Y389 deletions) have been previously described to be associated with renal disease. The prevalence of APOL1 variants in Saudi Arabia is unknown. We aimed to determine the prevalence of APOL1 variants in a cohort of patients with renal disease in Saudi Arabia. Patients with renal disease followed up at King Abdulaziz University Hospital were approached consecutively at the out patient clinic, and unaffected controls were approached at the blood donation area. Clinical and laboratory data were collected from electronic medical records. Laboratory variables in controls were obtained on enrollment. This is a cross-sectional, cohort study. One hundred and one patients with a mean age of 54.5 (±19) years, and 119 unaffected controls with a mean age of 31.9 (±7.89) years, were enrolled. Seventy-four patients (68.5%) had hypertension and 62 (57.4%) had diabetes. The mean estimated glomerular filtration rate was 22.47 (± 27.6) mL/min. Two patients were heterozygous for G1 allele. Among the control group, two were heterozygous for G1 allele, and three were heterozygous for G2. All five controls had no evidence of renal disease and no family history of renal disease. The prevalence of APOL1 genetic risk variants in the study cohort was very low. Larger studies are needed to determine the prevalence among renal disease patients in Saudi Arabia.
Muhammad Ismail Khan, Soyeon Choi, Muhammad Zahid, Habib Ahmad, Roshan Ali, Musharraf Jelani, and Changsoo Kang
Springer Science and Business Media LLC
Palmoplantar keratoderma (PPK) is a rare group of excessive skin disorder characterized by thickness over the palms and soles. The striate palmoplantar keratoderma (PPKS) is a form in which hyperkeratotic lesions are restricted to the pressure regions extending longitudinally in the length of each finger to the palm. Dominantly inherited mutations in genes including desmoglein 1, desmoplakin and keratin 1 have been suggested as genetic causes of PPKS. In this study, we investigated a three-generation Pakistani family segregating PPKS phenotype in autosomal dominant fashion to identify genetic cause in this family. We have performed whole-exome and Sanger sequencing followed by in silico bioinformatics analysis to pinpoint candidate mutation associated with PPK. Revealed a novel heterozygous mutation (NM_020882.2, COL20A1 c. 392C > G; p.Ser131Cys) in the loop region close to fibronectin type III-1 domain of the c ollagen 20 α1. This variant was not found in our in-house 219 ethnically matched Pakistani unaffected controls and showed minor allele frequency of 3.4 × 10−5 in Exome Aggregation Consortium database containing exome data of 59,464 worldwide individuals. It was assigned as “pathogenic” by in silico prediction tools. Previously, association of mutation in the COL14A1, one of the paralogous gene of COL20A1, with PPK was reported in the study with a Chinese family. Our study proposes COL20A1 gene as another potential candidate gene for PPKS which expand the spectrum of collagen proteins in the pathogenicity of PPK.
Abdul Wadood, Mehreen Ghufran, Ajmal Khan, Syed Sikander Azam, Musharraf Jelani, and Reaz Uddin
Elsevier BV
In the recent decades, the interest on glycosidases has dramatically increased, mainly because these enzymes play a vital role in many biological processes. Based on the biological potential associated to these enzymes, several glycosidase inhibitors have been developed. In this review, the most important inhibitors targeting these enzymes, including the disaccharides, iminosugars, monocyclic iminosugars, bicyclic iminosugars, thiosugars and carbasugars will be discussed and special attention will be given to the ones that are currently used clinically. This review summarizes and characterizes the current knowledge regarding the classes of glycosidase inhibitors that have therapeutic potential in a wide range of diseases. It highlights the patents, relevant research and patent applications filed in the past years in the field. Since the glycosidase inhibitors are involved in several chronic diseases and possibly pandemic, the pharmaceutical research towards developing new generations of these molecules is very important to public health. Most of the glycosidase inhibitors mimics the structures of monosaccharides or oligosaccharides and are well accepted by the organisms since they benefit from privileged drug-like properties. Disaccharides, iminosugars, carbasugars and thiosugars derivatives are the most popular inhibitors among the glycosidase inhibitors.
Abdul Wadood, Alam Jamal, Muhammad Riaz, Ajmal Khan, Reaz Uddin, Musharraf Jelani, and Syed Sikander Azam
Elsevier BV
Streptococcus pneumoniae (pneumococcus) is a Gram-positive bacterium. Humans are the major target for the pneumococcus. The pneumococcus is a common etiological agent of many different diseases such as bacterial meningitis, pneumonia, otitis media (OM), sinusitis, and conjunctivitis. According to the WHO, the pneumococcus is responsible for causing 1 million deaths each year. In 2000, over 14 million children worldwide under the age of 5 years were diagnosed with a pneumococcal disease, with the highest incidence seen in Africa. The human population most susceptible to pneumococcal infections is that of children due to their immature immune system. A sensational increase in antibiotic resistance among S. pneumoniae has been witnessed in different parts of the world since 1980s. The increase of resistance of S. pneumoniae to antibiotics is of major concern throughout the world. Worldwide, there are concerns about rising levels of antibiotic resistance and fears that the efficacy of antimicrobial therapy may be compromised, resulting in treatment failure and reduced utility of older antibiotics, a comparatively novel method has been used to defeat the resistant pathogens since last decade. The computational subtractive genomics approach is one of them, in which the bacterial pathogen complete proteins is gradually rock-bottom to a small number of likely drug targets. In this approach the steps which are used to find human non-homologs targets, proteins that are essential to the disease causing agent and participation of the selected proteins in pathogen metabolic pathways which are necessary for the survival of bacteria. We used computational subtractive genomics on consummate proteins of the of S. pneumonia strain JJA in this study and concluded with 2 proteins that can be used as potent drug targets against which new dynamic molecules can be planned to make better the action to treat the disease which is related with pathogen.
Jumana Yousuf Al-Aama, Hams Saeed Al-Zahrani, Musharraf Jelani, Hesham Salih Sabir, Saad Abdullah Al-Saeedi, and Saleem Ahmed
Wiley
Jumana Yousuf Al-Aama, Hams Saeed Al-Zahrani, Musharraf Jelani , Hesham Salih Sabir, Saad Abdullah Al-Saeedi, and Saleem Ahmed Princess Al-Jawhara Center of Excellence in Research of Hereditary Disorders, Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Pediatric Radiology Unit, Faculty of Medicine, and Pediatric Department, Faculty of Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
M.A.A.M. Jelani, D.A. Angus, and A.D. Booth
EAGE Publications BV
The evaluation of anisotropy parameters is demonstrated in the τ-p (intercept time – horizontal slowness) domain, using pre-stack seismic data. It allows critical slowness, of reflected energy to be identified, from which anisotropic parameters in a target layer can be extracted. However, geometric effects (e.g., horizon dip) can damage the accurate evaluation of the critical slowness, thereby impeding the accuracy of the anisotropy parameters. We simulate pre-stack seismic data from a basin province, featuring “seaward dipping reflector” (SDR) geometries. SDRS are formed by stacked volcanic layers; given the strong velocity contrast between volcanic and host rock, a strongly anisotropic fabric can be introduced. Our simulation delivers synthetic responses through an SDR package, with data in both shot and common-midpoint (CMP) domain supplied to the τ-p transform, include varying anisotropic strengths and dip angle of the uppermost SDR interface. Thus, we consider the accuracy of recovered anisotropy estimates. Our results show that models with similar induced anisotropic fabric but varying interface of uppermost SDR yield different critical slowness and hence, affecting the accuracy of extracting anisotropic parameter values. We propose that anisotropic parameters can be successfully recovered from pre-stack CMP data in the τ-p domain, with accuracy typically better than ±10%.
M.A.A.M. Jelani and A.D. Booth
EAGE Publications BV
The Orange Basin is located off the western margin of Southern Africa, formed during the Late Jurassic to Early Cretaceous by the break-up of Gondwana and the resultant separation of the African and South American. Such rift events are associated with volcanism that, in this case, presents as packages of so-called ‘seaward dipping reflectors’ (SDRs) formed of stacked basaltic flows. We use first arrival traveltimes recorded in a long-offset acquisition (10km) to develop a 2-D regional tomographic P-wave velocity model of the basin, and to constrain the seismic velocity structure of the SDRs across the continent-ocean transition (COT); for efficiency, these models are differently downsampled from the original acquisition. Both regional and local tomographic models show significant variation of typical velocity structure of a passive continental margin. First, we attempt to image the whole margin through a one-time-inversion. High velocities (3750-5000 m/s) in the final inverted model suggest the existence of basaltic flows, correctly positioned geographically with respect to their appearance in the seismic profile. Our method shows large potential for analyzing the internal architecture of passive continental margins to validate the existence of SDR packages and further advances are anticipated where it is integrated with a full-waveform inversion approach.
Fatma Dursun, Hussein Sheikh Ali Mohamoud, Noreen Karim, Muhammad Naeem, Musharraf Jelani, and Heves Kırmızıbekmez
Galenos Yayinevi
Perrault syndrome (PRLTS) is a heterogeneous group of clinical and genetic disorders characterized by sensory neuronal hearing loss in both sexes and premature ovarian failure or infertility in females. Neurological and hearing loss symptoms appear early in life, but female infertility cannot be detected before puberty. Spastic limbs, muscle weakness, delayed puberty and irregular menstrual cycles have also been observed in PRLTS patients. Mutations in five genes, i.e. HSD17B4, HARS2, CLPP, LARS2, and C10orf2, have been reported in five subtypes of PRLTS. Here, we report a milder phenotype of PRLTS in a Turkish family in which two affected patients had no neurological findings. However, both were characterized by sensory neuronal hearing loss and the female sibling had secondary amenorrhea and gonadal dysgenesis. Genome-wide homozygosity mapping using 300K single-nucleotide polymorphism microarray analysis together with iScan platform (Illumina, USA) followed by candidate gene Sanger sequencing with ABI 3500 Genetic Analyzer (Life Technologies, USA) were used for molecular diagnosis. We found a novel missense alteration c.624C>G; p.Ile208Met in exon 5 of the CLPP at chromosome 19p13.3. This study expands the mutation spectrum of CLPP pathogenicity in PRLTS type 3 phenotype.
Yaser Mohammad Alkhiary, Musharraf Jelani, Mona Mohammad Almramhi, Hussein Sheikh Ali Mohamoud, Rayan Al-Rehaili, Hams Saeed Al-Zahrani, Rehab Serafi, Huanming Yang, and Jumana Yousuf Al-Aama
Elsevier BV
Papillon–Lefevre syndrome (PALS) is a rare, autosomal recessive disorder characterized by periodontitis and hyperkeratosis over the palms and soles. Mutations in the cathepsin C gene (CTSC) have been recognized as the cause of PALS since the late 1990s. More than 75 mutations in CTSC have been identified, and phenotypic variability between different mutations has been described. Next generation sequencing is widely used for efficient molecular diagnostics in various clinical practices. Here we investigated a large consanguineous Saudi family with four affected and four unaffected individuals. All of the affected individuals suffered from hyperkeratosis over the palms and soles and had anomalies of both primary and secondary dentition. For molecular diagnostics, we combined whole-exome sequencing and genome-wide homozygosity mapping procedures, and identified a recurrent homozygous missense mutation (c.899G>A; p.Gly300Asp) in exon 7 of CTSC. Validation of all eight family members by Sanger sequencing confirmed co-segregation of the pathogenic variant (c.899G>A) with the disease phenotype. This is the first report of whole-exome sequencing performed for molecular diagnosis of PALS in Saudi Arabia. Our findings provide further insights into the genotype–phenotype correlation of CTSC pathogenicity in PALS.
Musharraf Jelani, Changsoo Kang, Hussein Sheikh Ali Mohamoud, Rayan Al-Rehaili, Mona Mohammad Almramhi, Rehab Serafi, Huanming Yang, Jumana Yousuf Al-Aama, Muhammad Naeem, and Yaser Mohammad Alkhiary
Elsevier BV
OBJECTIVES
The present study aimed to identify the genetic cause of non-syndromic primary failure of tooth eruption in a five-generation consanguineous Saudi family using whole-exome sequencing (WES) analysis.
DESIGN
The family pedigree and phenotype were obtained from patient medical records. WES of all four affected family members was performed using the 51 Mb SureSelect V4 library kit and then sequenced using the Illumina HiSeq2000 sequencing system. Sequence alignment, variant calling, and the annotation of single nucleotide polymorphisms and indels were performed using standard bioinformatics pipelines. The genotype of candidate variants was confirmed in all available family members by Sanger sequencing.
RESULTS
Pedigree analysis suggested that the inheritance was autosomal recessive. WES of all affected individuals identified a novel homozygous variant in exon 8 of the parathyroid hormone 1 receptor gene (PTH1R) (NM_000316: c.611T>A: p.Val204Glu).
CONCLUSION
To the best of our knowledge, this is the first report of primary failure of eruption caused by a homozygous mutation in PTH1R. Our findings prove the application of WES as an efficient molecular diagnostics tool for this rare phenotype and further broaden the clinical spectrum of PTH1R pathogenicity.
Nuha Alrayes, Hussein Sheikh Ali Mohamoud, Saleem Ahmed, Mona Mohammad Almramhi, Taghreed Mohammad Shuaib, Jun Wang, Jumana Yousuf Al-Aama, Kate Everett, Jamal Nasir, and Musharraf Jelani
Elsevier BV
Autosomal recessive primary microcephaly (MCPH) refers to a genetically heterogeneous group of neurodevelopmental disorders in which patients exhibit a marked decrease in occipitofrontal head circumference at birth and a variable degree of intellectual disability. To date, 18 genes have been reported for MCPH worldwide. We enrolled a consanguineous family from Saudi Arabia presenting with primary microcephaly, developmental delay, short stature and intellectual disability. Whole exome sequencing (WES) with 100× coverage was performed on two affected siblings after defining common regions of homozygosity through genome-wide single nucleotide polymorphism (SNP) microarray genotyping. WES data analysis, confirmed by subsequent Sanger sequence validation, identified a novel homozygous deletion mutation (c.967delA; p.Glu324Lysfs12*) in exon 10 of the alkylglycerol monooxygenase (AGMO) gene on chromosome 7p21.2. Population screening of 178 ethnically matched control chromosomes and consultation of the Exome Aggregation Consortium database, containing 60,706 individuals' exomes worldwide, confirmed that this mutation was not present outside the family. To the best of our knowledge, this is the first evidence of an AGMO mutation underlying primary microcephaly and intellectual disability in humans. Our findings further expand the genetic heterogeneity of MCPH in familial cases.