Publications by authors named "Muzammil Ahmad Khan"

22 Publications

  • Page 1 of 1

Alopecia-mental retardation syndrome: Molecular genetics of a rare neuro-dermal disorder.

Ann Hum Genet 2021 Apr 21. Epub 2021 Apr 21.

Gomal Centre of Biochemistry and Biotechnology, Gomal University, Dera Ismail Khan, KPK, Pakistan.

Alopecia-mental retardation syndrome (APMR) is a rare autosomal recessive neuro-dermal disorder. It is characterized by heterogeneous phenotypic features, that is, absence of hair on the scalp, eyelashes, and eyebrows and mild to severe intellectual disability. So far, approximately 14 families (i.e., Iranian, Pakistani, and Swiss) with APMR have been reported in the scientific literature. Its precise prevalence is still unknown, but according to a predictive estimate, it prevails with the ratio of 1 in 1,000,000 persons worldwide. Until now, only four loci (two characterized and two uncharacterized) have been reported to be involved in APMR. The pathogenic variants in alpha-2-HS-glycoprotein [AHSG; APMR1 (MIM#203650)] and lanosterol synthase [LSS; APMR4 (MIM#618840)] are the characterized genetic factors associated with APMR. Among them, AHSG was reported in a consanguineous Iranian family and LSS gene in a Swiss origin family, while the remaining two uncharacterized loci, that is, APMR2 and APMR3, are reported in the Pakistani population. The current mini-report discusses the molecular genetics and mutational spectrum of APMR syndrome, its differential diagnosis from related disorders, and prediction of plausible candidate genes in two uncharacterized loci.
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http://dx.doi.org/10.1111/ahg.12425DOI Listing
April 2021

Expression analysis of tumour necrosis factor alpha (TNF-α) and alkaline phosphatase in occupational workers exposed to low dose of X-radiation: A case-control study.

J Pak Med Assoc 2020 Nov;70(11):1887-1896

Gomal Centre of Biochemistry and Biotechnology, Gomal University, Dera Ismail Khan, KPK, Pakistan.

Objectives: To evaluate liver and inflammatory biomarkers in occupationally exposed radiology workers.

Methods: The descriptive study was conducted at Mufti Mehmood Memorial Teaching Hospital and Gomal Centre of Biochemistry and Biotechnology, Gomal University, Dera Ismail Khan, Pakistan, from September 2017 to May 2018, and comprised X-ray technicians working 48-72 hours per week, and a group of age- and gender-matched unexposed healthy controls. The exposed group was divided into three sub-groups based on their radiation work duration. Liver health status involved estimation of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase GGT and bilirubin through automated chemistry analyser, while serum tumour necrosis factor-alpha and interleukin- 6 levels through enzyme-linked immunosorbent assay technique. Relative gene expression analysis of tumour necrosis factor-alpha and alkaline phosphatase was performed through reverse transcription-polymerase chain reaction. Data was analysed using SPSS 20.

Results: Of the 70 subjects, 50(71.4%) were cases with a mean age of 36.98±8.07 years and 20(28.6%) were controls with a mean age of 36.80±7.78 years. Serum alanine aminotransferase and alkaline phosphatase levels showed significant elevation in the cases compared to the controls (p<0.0001), although alanine aminotransferase levels were within the normal range. The difference in aspartate aminotransferase, gamma-glutamyl transferase and bilirubin levels was not significant (p>0.05). Tumour necrosis factor-alpha concentration was significantly high in the cases compared to the controls (p<0.0001). In contrast with proteomic analysis, relative gene expression analysis revealed reduced level of alkaline phosphatase and tumour necrosis factor-alpha in the cases compared to the controls (p<0.05).

Conclusions: Serum proteomic analysis of X-ray technicians indicated acute inflammatory conditions, while genomic analysis exhibited down-regulation of alkaline phosphatase and tumour necrosis factor-alpha genes.
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http://dx.doi.org/10.5455/JPMA.10644DOI Listing
November 2020

Exome sequencing of a Pakistani family with spastic paraplegia identified an 18 bp deletion in the cytochrome B5 domain of FA2H.

Neurol Res 2021 Feb 27;43(2):133-140. Epub 2020 Nov 27.

Diagnostic and Research Institute of Human Genetics, Medical University of Graz , Graz, Austria.

Hereditary spastic paraplegias (HSPs) are a diverse class of neurodegenerative disorders that mainly affect the corticospinal tract of the body and result in various clinical conditions such as lower limb spasticity and muscle weakness in the lower extremities. Worldwide, more than 70 chromosomal loci/genes have been reported to be associated with HSPs, out of which, six genes viz., and have been mapped in Pakistani families. In the present genetic study, we report on a large consanguineous Pakistani family with a complex form of HSP segregating with a 18 bp deletion in the first exon of the Fatty Acid 2-Hydroxylase () gene (NM_024306.5:c.159_176del). The identified in-frame deletion results in loss of six amino acids (p.Arg53_Ile58del) within the cytochrome B5 domain of the protein. FA2H is required for alpha-hydroxylation of free fatty acids to form alpha-hydroxylated sphingolipids. Its cytochrome b5-like heme-binding domain, which spans from residues 15 to 85, imparts the redox activity to FA2H. This mutation has previously been reported in a Pakistani family presenting with a similar form of complex HSP. Together with our findings the pathogenic role of the observed variant is further supported. Mutation studies on additional Pakistani families for will further elucidate its mutational spectrum, which may help in developing a prenatal diagnostic test for Khyber Pakhtunkhwa resident Pakistani families.
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http://dx.doi.org/10.1080/01616412.2020.1831329DOI Listing
February 2021

Outcome associated with EPCAM founder mutation c.499dup in Qatar.

Eur J Med Genet 2020 Oct 28;63(10):104023. Epub 2020 Jul 28.

Diagnostic Genomic Division, Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, Doha, 3050, Qatar.

Tufting enteropathy (TE) is a rare autosomal recessive congenital enteropathy that usually requires long-term parenteral nutrition (PN). In the Arabic Peninsula, four distinct EPCAM mutations have been identified to cause TE. As consanguineous marriages are socially favored, pre-marital and pre-conception testing has become a critical disease prevention strategy. This study aimed to identify the pathogenic EPCAM mutations causing TE in Qatari families and determine possible genotype-phenotype correlations. Twenty-two TE patients from seven multiplex families with TE were identified. Blood samples were collected from patients and first-degree relatives. Exons of the gene were amplified and sequenced. Retrospective chart review and/or family interviews were conducted to determine phenotypic characteristics of the disease. Sequence analysis revealed a single, previously described c.499dup mutation in exon 5 of all families tested, suggesting a founder effect. Of the 18 patients whose full clinical information was available, three patients (17%) were off PN with a good quality of life, without intestinal transplantation, and one (6%) was receiving partial PN. Our patients with TE were severely stunted compared to a similar group of patients receiving long-term PN for short bowel syndrome, suggesting that this could possibly be due to TE rather than secondary to inadequate nutrition. Our study identified the EPCAM mutation c.499dup as the genetic defect causing TE in all the participant Qatari families. This finding should facilitate early diagnosis of TE and genetic counseling. Furthermore, it should aid in the prevention of TE through pre-marital screening, antenatal diagnosis, and pre-implantation genetic diagnosis.
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http://dx.doi.org/10.1016/j.ejmg.2020.104023DOI Listing
October 2020

Association of sequence variants in frizzled-6 with autosomal recessive nail dysplasia (NDNC-10) in Pashtun families.

J Pak Med Assoc 2020 Jan;70(1):143-146

Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan.

Primitive epidermis develops the nail apparatus. Nails have a strong and inflexible nail plate at the end of each digit. Very few genes responsible for causing nonsyndromic form of nail dysplasia have been reported. In the current study, peripheral blood samples were collectedfrom three unaffected individuals and four affectedindividuals of Family A, while blood from two affected and three unaffected individuals were taken of Family B. Genotyping in both the families was performed using highly polymorphic short tandem repeat microsatellite markers. Sanger sequence of the FZD6 gene was performed and analysed for segregation analysis. A comparative modelling approach was used to predict the three-dimensional structures of FZD-6 protein using Modeller 4. Linkage analysis mapped a disease locus on chromosome 8q22.3, harbouring FZD6. Targeted Sanger sequencing of all the coding exons of FZD6 revealed a nonsense sequence variant in pedigree A, whereas a missense sequence variant in pedigree B. Finding and literature indicates the disease spectrum of Pakistani population with claw-shaped nail dysplasia, particularly in families of Pashtun origin.
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http://dx.doi.org/10.5455/JPMA.9200DOI Listing
January 2020

Genetic study of Khyber-Pukhtunkhwa resident Pakistani families presenting primary microcephaly with intellectual disability.

J Pak Med Assoc 2019 Dec;69(12):1812-1816

Gomal Centre of Biochemistry and Biotechnology, Gomal University, D.I. Khan, Khyber Pakhtunkhwa, Pakistan.

Objective: To investigate the genetic factor responsible for causing microcephaly and determine allelic heterogeneity of Abnormal spindle microtubule gene.

Methods: The genetic study was conducted at the Kohat University of Science and Technology, Kohat, and Gomal University, D.I.Khan, Pakistan, during 2017-18, and comprised 5 consanguineous families from South Waziristan, Kurram Agency, Karak, Bannu and Dera Ismail Khan regions of the country's Khyber Pakhtukhwa province. Blood samples from all available and cooperative family members (including normal and affected) were obtained, and molecular analysis was carried out through whole genome single nucleotide polymorphisms genotyping, exome sequencing and Sanger sequencing.

Results: Of the 15 patients, 9(60%) were males and 6(40%) were females. Genetic mapping revealed linkage to the MCPH5 locus which harbours the microcephaly-associated abnormal spindle-like microcephaly gene. Mutation analysis of the gene identified missense mutation c.3978G>A (p.Trp1326*) in families A, B and C, a deletion mutation c.7782_7783delGA (p.(Lys2595Serfs*6)) in family D, and a splice site defect c.2936+5G>A in family E.

Conclusions: There was suggestion of strong founder effect of mutation c.3978G>A (p.Trp1326*).
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http://dx.doi.org/10.5455/JPMA.300681DOI Listing
December 2019

Exome sequence analysis in consanguineous Pakistani families inheriting Bardet-Biedle syndrome determined founder effect of mutation c.299delC (p.Ser100Leufs*24) in BBS9 gene.

Mol Genet Genomic Med 2019 08 11;7(8):e834. Epub 2019 Jul 11.

Institute of Human Genetics, Medical University of Graz, Graz, Austria.

Background: Bardet-Biedl syndrome (BBS) is characterized by a heterogeneous phenotypic spectrum of retinopathy, intellectual disability (ID), obesity, polydactyly, and kidney dysfunctions as the major clinical features. Genetic investigations have reported 21 BBS genes, the products of which are mostly located at the centrosome, basal body or the ciliary transition zone.

Methods: In the present genetic report, we analyzed two apparently unrelated consanguineous BBS families from Dera Ismail Khan (D.I.Khan) district, Pakistan. Genetic mapping was performed using Whole exome sequencing and Sanger sequencing.

Results: Whole exome sequencing identified a recently reported single base deletion NM_001033604.1:c.299delC in the fourth exon of BBS9 in both families. The identified frameshift mutation is predicted to cause premature truncation of the expressed protein (p.Ser100Leufs*24). This mutation has previously been mapped in a consanguineous Pakistani family; therefore this is the second report of this particular mutation in two additional BBS families originating from different locations.

Conclusion: We speculate the evolutionary significance of this mutation and assume its strong founder effect in the Khaisoori tribe of D.I.Khan. Based on these findings, we suggest developing a molecular diagnostic test that may be used for premarital and prenatal screening of families at risk of BBS.
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http://dx.doi.org/10.1002/mgg3.834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687644PMC
August 2019

Clinical Biomarkers for Diagnosis of Damages in Individuals with Long-Term Exposure to X-Rays.

J Coll Physicians Surg Pak 2019 Jul;29(7):616-620

Gomal Center of Biochemistry and Biotechnology, Gomal University, Dera Ismail Khan, KPK, Pakistan.

Objective: To determine altered manifestation of plasma proteins in X-rays technicians who are regularly exposed to low doses of radiations over a long period during their job.

Study Design: Descriptive study.

Place And Duration Of Study: District Headquarters Hospital and Mufti Mahmood Memorial Teaching Hospital; from January 2017 to January 2018.

Methodology: The study enrolled 70 individuals consisting of 50 X-ray technicians working 8 to 12 hours/day for five days per week and 20 unexposed healthy controls. The serum protein expression pattern (concentrations of various serum proteins) was evaluated through cellulose acetate electrophoresis and serum antioxidant status was measured through ferric reducing ability of plasma (FRAP) assay.

Results: The antioxidant assay showed significantly low trolox-equivalent antioxidant capacity (TEAC) status and FRAP value in X-ray technicians as compared to controls (p<0.001). Analysis of serum protein demonstrated a significantly reduced concentrations of albumin (p<0.001) and elevated level of the Ɣ-globulins (p<0.001), while other globulins fractions like α1 and β remain unchanged. There was a strong negative correlation (p<0.001) according to Pearson coefficient (r=87%⁽⁻⁾) between albumin and Ɣ-globulins fraction. Whereas, a positive correlation (p<0.001) (r=46%⁽⁺⁾) between alpha 1 globulin and albumin fraction was observed. A correlation between other globulin fractions and albumin was found statistically significant (p<0.001).

Conclusion: Elevated serum gamma globulins may be a potential protein biomarker for triage and detection of X-radiation induced damages.
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http://dx.doi.org/10.29271/jcpsp.2019.07.616DOI Listing
July 2019

Genetic studies of multiple consanguineous Pakistani families segregating oculocutaneous albinism identified novel and reported mutations.

Ann Hum Genet 2019 07 13;83(4):278-284. Epub 2019 Mar 13.

Gomal Centre of Biochemistry and Biotechnology, Gomal University, D.I. Khan, Pakistan.

Oculocutaneous albinism (OCA) is an autosomal-recessive disorder of a defective melanin pathway. The condition is characterized by hypopigmentation of hair, dermis, and ocular tissue. Genetic studies have reported seven nonsyndromic OCA genes, among which Pakistani OCA families mostly segregate TYR and OCA2 gene mutations. Here in the present study, we investigate the genetic factors of eight consanguineous OCA families from Pakistan. Genetic analysis was performed through single-nucleotide polymorphism (SNP) genotyping (for homozygosity mapping), whole exome sequencing (for mutation identification), Sanger sequencing (for validation and segregation analysis), and quantitative PCR (qPCR) (for copy number variant [CNV] validation). Genetic mapping in one family identified a novel homozygous deletion mutation of the entire TYRP1 gene, and a novel deletion of exon 19 in the OCA2 gene in two apparently unrelated families. In three further families, we identified homozygous mutations in TYR (NM_000372.4:c.1424G > A; p.Trp475*), NM_000372.4:c.895C > T; p.Arg299Cys), and SLC45A2 (NM_016180:c.1532C > T; p.Ala511Val). For the remaining two families, G and H, compound heterozygous TYR variants NM_000372.4:c.1037-7T > A, NM_000372.4:c.1255G > A (p.Gly419Arg), and NM_000372.4:c.1255G > A (p.Gly419Arg) and novel variant NM_000372.4:c.248T > G; (p.Val83Gly), respectively, were found. Our study further extends the evidence of TYR and OCA2 as genetic mutation hot spots in Pakistani families. Genetic screening of additional OCA cases may also contribute toward the development of Pakistani specific molecular diagnostic tests, genetic counseling, and personalized healthcare.
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http://dx.doi.org/10.1111/ahg.12307DOI Listing
July 2019

Pakistan Genetic Mutation Database (PGMD); A centralized Pakistani mutome data source.

Eur J Med Genet 2018 Apr 7;61(4):204-208. Epub 2017 Dec 7.

Department of Biotechnology & Genetic Engineering, Kohat University of Science & Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan. Electronic address:

The development and advancement of next generation sequencing have not only sped up the process of identifying rare variants, but have also enabled scientists to explore all variants in a single individual. The Pakistani population has a high ratio of first degree consanguinity, which is why it is a rich source for various kinds of genetic disorders. Due to the heterogeneous composition of Pakistani population, the likelihood of genetic heterogeneity for each disorder is high. Therefore, the compilation and organization of such vast genetic data is necessary to facilitate access for analysis and interpretation to researchers and medical geneticists. The increased research on Pakistani ethnic families for disease gene identification has revealed many mutations, which has led us to develop a Pakistani mutome database entitled "Pakistan Genetic Mutation Database (PGMD)". In PGMD, the medico-genetic information about diseases are mainly compiled into Syndromic and Non-syndromic disorders. It is a public database, which can be freely accessed from http://www.pakmutation.com. At present, we have registered more than 1000 mutations, reported in about 130 different kinds of genetic disorders. Practically, PGMD will assist researchers, clinicians, and geneticists in genetic counseling and screening of population-specific mutations, which will also aid in personalized healthcare.
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http://dx.doi.org/10.1016/j.ejmg.2017.11.015DOI Listing
April 2018

Molecular genetic analysis of consanguineous families with primary microcephaly identified pathogenic variants in the ASPM gene.

J Genet 2017 Jun;96(2):383-387

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar.

Autosomal recessive primary microcephaly is a rare genetic disorder that is characterized by reduced head circumference and a varying degree of intellectual disability. Genetic studies on consanguineous families with primary microcephaly have identified 15 (MCPH) causative genes that include MCPH1, WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1, CDK6, CENPE, SASS6 MFSD2A ANKLE2 and CIT (Khan et al. 2014; Yamamoto et al. 2014; Alakbarzade et al. 2015;Morris-Rosendahl and Kaindl 2015; Basit et al. 2016). Physiologically, most of these MCPH proteins are involved in cell cycle and its regulation. In the present clinical genetic study, we have present two consanguineous Pakistani families segregating primary microcephaly and intellectual disability. These families were ascertained from the Saraiki ethnic part of Khyber-Pakhtunkhwa province in Pakistan. Whole exome sequencing in one family revealed a novel 1-bp deletion NM_018136.4: c.10013delA (p.Asp3338Valfs*2), while the other family showed a previously reported nonsense mutation NM_018136.4: c.9730C>T (rs199422195 (p.Arg3244*)) in ASPM gene. The novel frame-shift mutation (p.Asp3338Valfs*2) in ASPM presumably truncates the protein synthesis that results in loss of armadillo-type fold domain.
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http://dx.doi.org/10.1007/s12041-017-0759-xDOI Listing
June 2017

Comment on homozygosity mapping of a consanguineous Pakistani family affected with oculocutaneous albinism to gene.

Int J Ophthalmol 2017 18;10(5):826. Epub 2017 May 18.

Gomal Centre of Biochemistry and Biotechnology, Gomal University, Dera Ismail Khan, KPK 29050, Pakistan.

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http://dx.doi.org/10.18240/ijo.2017.05.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437477PMC
May 2017

Ophthalmo-genetic analysis of Pakistani patients with nonsyndromic oculocutaneous albinism through whole exome sequencing.

J Pak Med Assoc 2017 May;67(5):790-792

Gomal Centre of Biochemistry and Biotechnology, Gomal University, Dera Ismail Khan, KPK, Pakistan.

Oculocutaneous albinism (OCA) is a disorder of defective melanin biosynthesis that is characterized by hypo-pigmentation of skin, hair and retinal pigment epithelium. Phenotypically, OCA patients exhibit white milky skin, whitish to golden hair and deterioration of retinal cells. Until recently, genetic studies have reported seven causative genes (TYR, TYRP1, OCA2, SLC45A2, SLC24A2, C10ORF11 and MCIR) and an uncharacterized OCA5 locus. Herein we present the medico-genetic study of three Pakistani patients inheriting autosomal recessive OCA. Whole exome sequencing, followed by Sanger DNA sequencing for segregation analysis, revealed recurrent mutations c.346C>T (p.Arg116*) and c.1255G>A (p.Gly419Arg) (family A and B respectively) in TYR gene, while the patient from family C did not reveal any known gene mutation, which suggests the involvement of some novel genetic factor. It is the first report of mapping c.346C>T mutation in a Pakistani patient. Our study further extends the evidence of genetic hotspots regions in TYR gene causing OCA in Pakistani population.
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May 2017

A novel mutation in homeobox DNA binding domain of HOXC13 gene underlies pure hair and nail ectodermal dysplasia (ECTD9) in a Pakistani family.

BMC Med Genet 2017 04 12;18(1):42. Epub 2017 Apr 12.

Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, 26000, Khyber Pakhtunkhwa, Pakistan.

Background: Pure hair and nail ectodermal dysplasia (PHNED) is a congenital disorder of hair abnormalities and nail dysplasia. Both autosomal recessive and dominant inheritance fashion of PHNED occurs. In literature, to date, five different forms of PHNED have been reported at molecular level, having three genes known and two loci with no gene yet.

Methods: In this study, a four generations consanguineous family of Pakistani origin with autosomal recessive PHNED was investigated. Affected members exhibited PHNED phenotypes with involvement of complete hair loss and nail dysplasia. To screen for mutation in the genes (HOXC13, KRT74, KRT85), its coding exons and exons-intron boundaries were sequenced. The 3D models of normal and mutated HOXC13 were predicted by using homology modeling.

Results: Through investigating the family to known loci, the family was mapped to ectodermal dysplasia 9 (ECTD9) loci with genetic address of 12q13.13. Mutation screening revealed a novel missense mutation (c.929A > C; p.Asn310Thr) in homeobox DNA binding domain of HOXC13 gene in affected members of the family. Due to mutation, loss of hydrogen bonding and difference in potential energy occurs, which may resulting in alteration of protein function.

Conclusion: This is the first mutation reported in homeodomain, while 5 mutation reported in HOXC13 gene causing PHNED.
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http://dx.doi.org/10.1186/s12881-017-0402-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389142PMC
April 2017

The Molecular Genetics of Autosomal Recessive Nonsyndromic Intellectual Disability: a Mutational Continuum and Future Recommendations.

Ann Hum Genet 2016 Nov;80(6):342-368

Genomic Core Facility, Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, 3050, Qatar.

Intellectual disability (ID) is a clinical manifestation of the central nervous system without any major dysmorphologies of the brain. Biologically it affects learning capabilities, memory, and cognitive functioning. The basic defining features of ID are characterized by IQ<70, age of onset before 18 years, and impairment of at least two of the adaptive skills. Clinically it is classified in a syndromic (with additional abnormalities) and a nonsyndromic form (with only cognitive impairment). The study of nonsyndromic intellectual disability (NSID) can best explain the pathophysiology of cognition, intelligence and memory. Genetic analysis in autosomal recessive nonsyndrmic ID (ARNSID) has mapped 51 disease loci, 34 of which have revealed their defective genes. These genes play diverse physiological roles in various molecular processes, including methylation, proteolysis, glycosylation, signal transduction, transcription regulation, lipid metabolism, ion homeostasis, tRNA modification, ubiquitination and neuromorphogenesis. High-density SNP array and whole exome sequencing has increased the pace of gene discoveries and many new mutations are being published every month. The lack of uniform criteria has assigned multiple identifiers (or accession numbers) to the same MRT locus (e.g. MRT7 and MRT22). Here in this review we describe the molecular genetics of ARNSID, prioritize the candidate genes in uncharacterized loci, and propose a new nomenclature to reorganize the mutation data that will avoid the confusion of assigning duplicate accession numbers to the same ID locus and to make the data manageable in the future as well.
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http://dx.doi.org/10.1111/ahg.12176DOI Listing
November 2016

Genetic analysis of consanguineous families presenting with congenital ocular defects.

Exp Eye Res 2016 05 16;146:163-171. Epub 2016 Mar 16.

Department of Pediatrics, University of California, San Francisco, CA, USA. Electronic address:

Anophthalmia and microphthalmia (A/M) are a group of rare developmental disorders that affect the size of the ocular globe. A/M may present as the sole clinical feature, but are also frequently found in a variety of syndromes. A/M is genetically heterogeneous and can be caused by chromosomal aberrations, copy number variations and single gene mutations. To date, A/M has been caused by mutations in at least 20 genes that show different modes of inheritance. In this study, we enrolled eight consanguineous families with A/M, including seven from Pakistan and one from India. Sanger and exome sequencing of DNA samples from these families identified three novel mutations including two mutations in the Aldehyde Dehydrogenase 1 Family Member A3 (ALDH1A3) gene, [c.1310_1311delAT; p.(Tyr437Trpfs*44) and c.964G > A; p.(Val322Met)] and a single missense mutation in Forkhead Box E3 (FOXE3) gene, [c.289A > G p.(Ile97Val)]. Additionally two previously reported mutations were identified in FOXE3 and in Visual System Homeobox 2 (VSX2). This is the first comprehensive study on families with A/M from the Indian subcontinent which provides further evidence for the involvement of known genes with novel and recurrent mutations.
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http://dx.doi.org/10.1016/j.exer.2016.03.014DOI Listing
May 2016

Genetics of human isolated acromesomelic dysplasia.

Eur J Med Genet 2016 Apr 27;59(4):198-203. Epub 2016 Feb 27.

Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University Islamabad, Pakistan.

Acromesomelic dysplasia is a type of skeletal malformation affecting distal and middle segments of the extremities. It occurs in both isolated (non-syndromic) and syndromic forms. In later case, it shows association with cardiac, respiratory, neurological and genital abnormalities. Acromesomelic dysplasia segregates in autosomal recessive mode. Mutations in three genes (GDF5, NPR2, BMPR1B) have been reported to cause different forms of acromesomelic dysplasia. In the present review, we have discussed clinical spectrum, genetics and signalopathies of isolated acromesomelic dysplasias.
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http://dx.doi.org/10.1016/j.ejmg.2016.02.011DOI Listing
April 2016

Homozygosity mapping identified a novel protein truncating mutation (p.Ser100Leufs*24) of the BBS9 gene in a consanguineous Pakistani family with Bardet Biedl syndrome.

BMC Med Genet 2016 Feb 4;17:10. Epub 2016 Feb 4.

Institute of Human Genetics, Medical University of Graz, Graz, 8010, Austria.

Background: Bardet Biedl Syndrome (BBS) is a rare condition of multi-organ dysfunction with characteristic clinical features of retinal degeneration, truncal obesity, postaxial polydactyly, genital anomaly, intellectual disability and renal dysfunction. It is a hetero-genetic disorder and nineteen BBS genes have been discovered so far.

Methods: Whole genome SNP genotyping was performed by using CytoScan® 750 K array (Affymetrix). Subsequently, the segregation of the disease locus in the whole family was carried out by genotyping STS markers within the homozygous interval. Finally, the mutation analysis was performed by Sanger DNA sequencing.

Results: In the present molecular study a consanguineous Pakistani family, with autosomal recessive BBS, was analyzed. The clinical analysis of affected individuals presented with synpolydactyly, obesity, intellectual disability, renal abnormality and retinitis pigmentosa. The presented phenotype was consistent with the major features of BBS syndrome. Homozygosity mapping identified a common homozygous interval within the known BBS9 locus. Sequence analysis of BBS9/PTHB1 gene revealed a single base deletion of c.299delC (p.Ser100Leufs*24) in exon 4. This frame-shift mutation presumably leads to a 122 amino acid truncated protein with complete loss of its C-terminal PTHB1 domain in combination with a partial loss of the N-terminal PTHB1 domain as well. BBS9/PTHB1 gene mutations have been shown to be associated with BBS syndrome and to the best of our knowledge this study reports the first Pakistani family linked to the BBS9 gene.

Conclusion: Our molecular findings expand the mutational spectrum of BBS9 gene and also explain the genetic heterogeneity of Pakistan families with BBS syndrome. The growing number of mutations in BBS genes in combination with a detailed phenotypical description of patients will be helpful for genotype-phenotype correlation, targeted genetic diagnosis, prenatal screening and carrier testing of familial and non-familial BBS patients.
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http://dx.doi.org/10.1186/s12881-016-0271-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743198PMC
February 2016

Genetic analysis of a consanguineous Pakistani family with Leber congenital amaurosis identifies a novel mutation in GUCY2D gene.

J Genet 2014 Aug;93(2):527-30

Gomal Centre of Biochemistry and Biotechnology, Gomal University Dera Ismail Khan, Khyber-Pakhtoonkhwa 29050, Pakistan.

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http://dx.doi.org/10.1007/s12041-014-0394-8DOI Listing
August 2014

Mutation in NSUN2, which encodes an RNA methyltransferase, causes autosomal-recessive intellectual disability.

Am J Hum Genet 2012 May 26;90(5):856-63. Epub 2012 Apr 26.

Molecular Neuropsychiatry & Development Lab, Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Canada.

Causes of autosomal-recessive intellectual disability (ID) have, until very recently, been under researched because of the high degree of genetic heterogeneity. However, now that genome-wide approaches can be applied to single multiplex consanguineous families, the identification of genes harboring disease-causing mutations by autozygosity mapping is expanding rapidly. Here, we have mapped a disease locus in a consanguineous Pakistani family affected by ID and distal myopathy. We genotyped family members on genome-wide SNP microarrays and used the data to determine a single 2.5 Mb homozygosity-by-descent (HBD) locus in region 5p15.32-p15.31; we identified the missense change c.2035G>A (p.Gly679Arg) at a conserved residue within NSUN2. This gene encodes a methyltransferase that catalyzes formation of 5-methylcytosine at C34 of tRNA-leu(CAA) and plays a role in spindle assembly during mitosis as well as chromosome segregation. In mouse brains, we show that NSUN2 localizes to the nucleolus of Purkinje cells in the cerebellum. The effects of the mutation were confirmed by the transfection of wild-type and mutant constructs into cells and subsequent immunohistochemistry. We show that mutation to arginine at this residue causes NSUN2 to fail to localize within the nucleolus. The ID combined with a unique profile of comorbid features presented here makes this an important genetic discovery, and the involvement of NSUN2 highlights the role of RNA methyltransferase in human neurocognitive development.
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http://dx.doi.org/10.1016/j.ajhg.2012.03.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376419PMC
May 2012

Mutations in the alpha 1,2-mannosidase gene, MAN1B1, cause autosomal-recessive intellectual disability.

Am J Hum Genet 2011 Jul;89(1):176-82

Molecular Neuropsychiatry and Development Lab, Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

We have used genome-wide genotyping to identify an overlapping homozygosity-by-descent locus on chromosome 9q34.3 (MRT15) in four consanguineous families affected by nonsyndromic autosomal-recessive intellectual disability (NS-ARID) and one in which the patients show additional clinical features. Four of the families are from Pakistan, and one is from Iran. Using a combination of next-generation sequencing and Sanger sequencing, we have identified mutations in the gene MAN1B1, encoding a mannosyl oligosaccharide, alpha 1,2-mannosidase. In one Pakistani family, MR43, a homozygous nonsense mutation (RefSeq number NM_016219.3: c.1418G>A [p.Trp473*]), segregated with intellectual disability and additional dysmorphic features. We also identified the missense mutation c. 1189G>A (p.Glu397Lys; RefSeq number NM_016219.3), which segregates with NS-ARID in three families who come from the same village and probably have shared inheritance. In the Iranian family, the missense mutation c.1000C>T (p.Arg334Cys; RefSeq number NM_016219.3) also segregates with NS-ARID. Both missense mutations are at amino acid residues that are conserved across the animal kingdom, and they either reduce k(cat) by ∼1300-fold or disrupt stable protein expression in mammalian cells. MAN1B1 is one of the few NS-ARID genes with an elevated mutation frequency in patients with NS-ARID from different populations.
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http://dx.doi.org/10.1016/j.ajhg.2011.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135808PMC
July 2011

A novel deletion mutation in the TUSC3 gene in a consanguineous Pakistani family with autosomal recessive nonsyndromic intellectual disability.

BMC Med Genet 2011 Apr 22;12:56. Epub 2011 Apr 22.

Department of Biochemistry, Quaid-i-Azam University Islamabad, Islamabad, Pakistan.

Background: Intellectual disability (ID) is a serious disorder of the central nervous system with a prevalence of 1-3% in a general population. In the past decades, the research focus has been predominantly on X-linked ID (68 loci and 19 genes for non syndromic X linked ID) while for autosomal recessive nonsyndromic ID (NSID) only 30 loci and 6 genes have been reported to date.

Methods: Genome-wide homozygosity mapping with 500 K Nsp1 array (Affymetrix), CNV analysis, PCR based breakpoint mapping and DNA sequencing was performed to explore the genetic basis of autosomal recessive nonsyndromic ID in a large Pakistani family.

Results: Data analysis showed linkage at 8p23 locus with common homozygous region between SNPs rs6989820 and rs2237834, spanning a region of 12.494 Mb. The subsequent CNV analysis of the data revealed a homozygous deletion of 170.673 Kb which encompassed the TUSC3 gene.

Conclusion: We report a novel deletion mutation in TUSC3 gene which is the second gene after TRAPPC9 in which mutation has been identified in more than one family with autosomal recessive NSID. The study will aid in exploring the molecular pathway of cognition.
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http://dx.doi.org/10.1186/1471-2350-12-56DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096909PMC
April 2011