Are we geared for the upcoming challenges by nCoV-19 or is it still grim news…?

The novel Corona Virus (nCoV-2019), clouded the entire world during the year 2020; with its emergence in December 2019 from Wuhan, China. The nCoV-19 is a novel variant of the Coronavirus family, with its predecessors been implicated for the pandemics of Middle East Respiratory Syndrome (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS-CoV); that caused flu-like condition and respiratory distress symptoms [1-6]. The viral strain also intrudes on extra-pulmonary relevance; being involved with deranging immunity as evidenced by lymphopenia and a prolonged prothrombin time; it impacts cardiomyocytes and pancreatic tissue directly [7-11]. These implications of nCoV-19 does suggest a long-term relevance of the disease profile. The emergenceof nCoV-2019 was quick to gain a pandemic status worldwide. An immense shift in the influx of the type of patients was observed, that imparted a false impression of a reduction in cardiovascular and metabolic patient presentation; formerly that had been the majority engaging the worlds’ healthcare facility. But as the world prepares itself for a possible second wave of the n-CoV-19, a prudent approach would be to remind us of the history lessons from the previous corona-led pandemic, such as MERS and SARS. This editorial will emphasize on channeling our focus to nCoV-19 implications on cardiovascular and metabolic disorders. The pandemics of SARS-CoV during 2002-2003 and MERS-CoV in 2012 highlight the long term relevance of coronavirus to cardiac and metabolic disease pathologies, both during and in the aftermath of these pandemics [3]. The SARS-CoV had demonstrated an increase of cardiovascular problems by 44%, hyperlipidemia by 68% and diabetes mellitus by 60%, in people who had recovered from the viral attack [12, 13]. Likewise, MERS-CoV had also embarked an increase of cardiac disorders by 30% and hypertension by 50% and diabetes mellitus by 50% [3, 8, 9]. Published research on nCoV-19 has hinted for a similar rising trend of cardiovascular and metabolic complexities. An increase in cardiac troponin level is observed with increased cases of myocarditis and heart failure [14]. A 20% increase in the incidence of diabetes and a 40 % rise in cardiovascular and cerebrovascular diseases is observed with nCoV-19 [8, 9]. Little do we comprehend that the involvement of angiotensin converting enzyme 2 (ACE2) receptors could play havoc on endothelium, kidney, intestine, liver and any other organ [15]. The nCoV-19 has thrown a curveball to the realm of the worldwide health and financial setting. Even with the current economic predicament it does seems prudent to be prepared in advance for the long term consequences of this pandemic. The bigger question would be to, not just direct our efforts at countering the possible second wave of nCoV-19 but also for the possible chaos of cardiovascular and metabolic disease outfall, impacting the world health system.

Genetic Mapping and Mutation Analysis of Genes Causing Human Hereditary Skeletal Disorders

Genetic defects in the complex processes of embryonic development of the skeleton and its postnatal maintenance result in different types of clinically diverse and genetically heterogeneous skeletal disorders. This presents a diagnostic challenge because of their nonspecific presentation, variable clinical features, highly overlapping phenotypes and lack of recognition as a discrete clinical entity. The research work, presented in this dissertation, describes clinical and molecular investigations of fourteen families (A-N) segregating various forms of skeletal disorders in autosomal recessive pattern. Clinical examinations were performed at local Government hospitals. Blood samples were collected from both affected and unaffected members of the families. Genomic DNA, extracted from the blood samples, was used for microsatellite and SNP based genetic mapping and whole exome and chain termination sequencing. Clinical features, observed in affected members of six families (A-F), were analogous to a condition named as mucopolysaccharidosis. Linkage in these families was established to chromosome 16q24.3 harboring GALNS gene. Sanger sequencing revealed two novels (p.Phe216Ser, p.Glu121Argfs*37) and two previously reported mutations (p.Pro420Arg, p.Arg386Cys) in GALNS gene in the six families. In silico analysis predicted that the missense mutations affect structure and function of the GALNS protein. Clinical and radiographic examinations of affected members in three families (G-I) underscored the manifestations of acromesomelic dysplasia. Microsatellite based genotyping followed by sequence analysis of the NPR2 gene identified three novel missense mutations (p.Arg749Trp, p.Arg601Ser, p.Leu314Arg) in the families. Human genome scan using SNP microarray followed by exome sequencing discovered a potentially casual frameshift mutation (c.594-595insT; p.Gln198Thrfs*21) in a novel gene KIAA0825 in the family J segregating post-axial polydactyly in an autosomal recessive manner. Affected individuals in family K exhibited peculiar clinical features including post axial polydactyly, speech impairment, hearing impairment of variable degree and proportionate short stature. This condition represented mild form of Joubert Abstract Genetic Mapping and Mutation Analysis of Genes Causing Human Hereditary Skeletal Disorders XVIII syndrome. Whole exome sequencing in the family revealed a novel in-frame deletion mutation (c.1115-1117delCCT; p.Ser372del) in the MKS1 gene. In silico analysis revealed that Ser372 residue resides in the “B9” interacting region of the MKS1 protein and inframe mutation (p.Ser372del) causes alteration in the conformation of mutant protein with two extra α helixes. The present study described three families (L-N) with split hand/foot malformations. In two families (L, M), genetic mapping followed by Sanger sequencing detected a novel frameshift mutation (c.300-306dupAGGGCGG; p.Leu103Argfs*52) in the WNT10B gene. In the third family (N), whole exome sequencing accompanied by SNP microarray, identified six nucleotides duplication (c.217-222dupCACCCG; p.His73_Pro74dup) in a novel causative gene HOXD8. The work presented in the dissertation resulted in the following publications. 1. Irfanullah, Saadullah Khan, Imran Ullah, C. Arnoud Meijer, Marlies Laurense Bik, Johan T den Dunnen, Claudia AL Ruivenkamp, Marriët JTV Hoffer, Gijs WE Santen, Wasim Ahmad (2016). Hypomorphic MKS1 mutation in a Pakistani family with mild Joubert syndrome and atypical features: expanding the phenotypic spectrum of MKS1-related ciliopathies. American Journal of Medical Genetics Part A 9999A:1–5 2. Irfanullah, Muhammad Umair, Saadullah Khan, Wasim Ahmad (2015). Homozygous Sequence Variants in the NPR2 Gene Underlying Acromesomelic Dysplasia Maroteaux Type (AMDM) in Consanguineous Families. Annals of Human Genetics 79: 238–244 3. Abdul Aziz, Irfanullah, Saadullah khan, Faridullah khan zimri, Noor Muhammad, Sajid Rashid, Wasim Ahmad (2014). Novel homozygous mutations in the WNT10B gene underlying autosomal recessive split hand/foot malformation in three consanguineous families. Gene 534: 265–271. 4. Irfanullah, Abdul Nasir, Sarmad Mahmood, Sohail Ahmed, Muhammad Ikram Ullah, Asmat Ullah, Abdul Aziz, Syed Irfan Raza, Khadim Shah, Saadullah Khan, Muhammad Jawad Hassan, Wasim Ahmad (2016). Identification and in silico analysis of GALNS mutations causing Morquio A syndrome in eight consanguineous families. Turkish Journal of Biology: DOI:10.3906/biy-1607-81 Abstract Genetic Mapping and Mutation Analysis of Genes Causing Human Hereditary Skeletal Disorders XIX 5. Asmat Ullah, Ajab Gul, Muhammad Umair, Irfanullah, Abdul Wali, Farooq Ahmad, Abdul Aziz, Wasim Ahmad (2017). Homozygous sequence variants in the WNT10B gene underlie split hand/foot malformation. Genetics and Molecular Biology (Submitted) 6. Irfanullah, Muhammad Ansar, Saadullah Khan, Abdul Aziz, Wasim Ahmad. Exome sequencing revealed a novel gene KIAA0825 underlying autosomal recessive postaxial polydactyly (In Preparation). 7. Irfanullah, Saadullah Khan, Maaike Verschuren, Marlies Laurense Bik, Johan T den Dunnen, Claudia AL Ruivenkamp, Marriët JTV Hoffer, Gijs WE Santen, Wasim Ahmad. Human HOXD8 is a novel candidate gene causing autosomal recessive split hand foot malformation in a large Pakistani consanguineous family (In Preparation) 8. Irfanullah, Syed Zohaib Tayyed Gilani, Saadullah Khan, Wasim Ahmad. Homozygous mutations in NPR2 gene underlying Acromesomelic dysplasia in Pakistani families (In preparation)