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1.
Clin Dysmorphol ; 29(1): 17-23, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31469663

RESUMO

Bardet-Biedl syndrome (BBS) is characterized by six major features: postaxial polydactyly, obesity, learning disabilities, renal anomalies, retinitis pigmentosa and hypogonadism and is inherited in an autosomal recessive manner. BBS is caused by disease causing sequence variants in the 22 BBS genes identified to date. In the present study, a single consanguineous Pakistani Family with BBS was clinically and genetically characterized. After establishing linkage to a BBS gene on chromosome 4q27, Sanger sequencing was performed in all available affected and unaffected members. Sequence analysis of the BBS7 gene revealed novel substitution mutation (c.719G>T; p. Gly240Val). Our findings further extend the body of evidence implicating BBS7 in causing BBS and expand the mutation spectrum.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31621941

RESUMO

Polydactyly is one of the most common congenital abnormal phenotype of autopod, which is characterized by extra supernumerary digit in hands/feet with or without well-developed bony structure within the digits. Preaxial polydactyly (PPD), postaxial polydactyly (PAP), and meso-axial (central) polydactyly are three different isoforms of polydactyly. Genetically, at least 10 genes have been identified causing nonsyndromic polydactyly. In the present study, we have investigated a large family segregating autosomal dominant form of nonsyndromic polydactyly. Whole exome sequencing followed by Sanger sequencing revealed a novel heterozygous missense variant (NM_005269.3; c.1064C>A; p.(Thr355Asn) in the gene GLI1 segregating with the disease phenotype within the family. This study presents first familial case of autosomal dominant form of polydactyly caused by the GLI1 variant.

3.
Genet Test Mol Biomarkers ; 23(10): 744-750, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31573334

RESUMO

Background: Greig cephalopolysyndactyly syndrome (GCPS) is a disorder of autopod and craniofacial abnormalities. Autopod anomalies include preaxial and/or postaxial polydactyly together with or without syndactyly while craniofacial features include hypertelorism and macrocephaly. GCPS is inherited in an autosomal dominant manner and is caused by sequence variants in GLI3. Methodology and Results: In this study, we examined four unrelated families with GCPS segregating in an autosomal dominant manner. Sanger sequencing revealed three novel (p.Tyr146Leufs*19, p.Glu99Serfs*60, and p.Thr541Arg) and one previously reported non-sense variant (p.Arg792*) in GLI3. Conclusion: The study expands the spectrum of the variants in the GLI3 gene linked to GCPS, and should also facilitate genetic counseling of GCPS patients in the Pakistani population.

4.
BMC Med Genet ; 20(1): 152, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488071

RESUMO

BACKGROUND: Consanguine families display a high degree of homozygosity which increases the risk of family members suffering from autosomal recessive disorders. Thus, homozygous mutations in monogenic obesity genes may be a more frequent cause of childhood obesity in a consanguineous population. METHODS: We identified 23 probands from 23 Pakistani families displaying autosomal recessive obesity. We have previously excluded mutations in MC4R, LEP and LEPR in all probands. Using a chip-based, target-region capture array, 31 genes involved in monogenic forms of obesity, were screened in all probands. RESULTS: We identified 31 rare non-synonymous possibly pathogenic variants (28 missense and three nonsense) within the 31 selected genes. All variants were heterozygous, thus no homozygous pathogenic variants were found. Two of the rare heterozygous nonsense variants identified (p.R75X and p.R481X) were found in BBS9 within one proband, suggesting that obesity is caused by compound heterozygosity. Sequencing of the parents supported the compound heterozygous nature of obesity as each parent was carrying one of the variants. Subsequent clinical investigation strongly indicated that the proband had Bardet-Biedl syndrome. CONCLUSIONS: Mutation screening in 31 genes among probands with severe early-onset obesity from Pakistani families did not reveal the presence of homozygous obesity causing variants. However, a compound heterozygote carrier of BBS9 mutations was identified, indicating that compound heterozygosity must not be overlooked when investigating the genetic etiology of severe childhood obesity in populations with a high degree of consanguinity.


Assuntos
Consanguinidade , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Obesidade Pediátrica/genética , Síndrome de Bardet-Biedl/genética , Índice de Massa Corporal , Pré-Escolar , Códon sem Sentido , Feminino , Genótipo , Heterozigoto , Homozigoto , Humanos , Leptina/genética , Masculino , Mutação , Paquistão , Obesidade Pediátrica/fisiopatologia , Linhagem , Receptor Tipo 4 de Melanocortina/genética , Receptores para Leptina/genética
5.
Ann Hum Genet ; 83(6): 477-482, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31173343

RESUMO

Ciliopathies are a clinically and genetically heterogeneous group of disorders often exhibiting phenotypic overlap and caused by abnormalities in the structure or function of cellular cilia. As such, a precise molecular diagnosis is important for guiding clinical management and genetic counseling. In the present study, two Pakistani families comprising individuals with overlapping clinical features suggestive of a ciliopathy syndrome, including intellectual disability, obesity, congenital retinal dystrophy, and hypogonadism (in males), were investigated clinically and genetically. Whole-exome sequencing identified the likely causes of disease as a novel homozygous frameshift mutation (NM_152384.2: c.196delA; p.(Arg66Glufs*12); family 1) in BBS5, and a nonsense mutation (NM_019892.5:c.1879C>T; p.Gln627*; family 2) in INPP5E, previously reported in an extended Pakistani family with MORM syndrome. Our findings expand the molecular spectrum associated with BBS5 mutations in Pakistan and provide further supportive evidence that the INPP5E mutation is a common cause of ciliopathy in Northern Pakistan, likely representing a regional founder mutation. This study also highlights the value of genomic studies in Pakistan for families affected by rare heterogeneous developmental disorders and where clinical phenotyping may be limited by geographical and financial constraints. The identification of the spectrum and frequency of disease-causing variants within this setting enables the development of population-specific genetic testing strategies targeting variants common to the local population and improving health care outcomes.

6.
Eur J Med Genet ; 62(8): 103688, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31152918

RESUMO

Mesoaxial synostotic syndactyly (MSSD) with phalangeal reduction is an uncommon congenital limb abnormality characterized by central osseous synostosis at a metacarpal level, mesoaxial reduction of the fingers, and preaxial cutaneous syndactyly in toes. In rare cases, the disease is also associated with fifth finger clinodactyly and postaxial polydactyly. It has autosomal recessive inheritance pattern caused by homozygous variants in the gene BHLHA9 mapped at chromosome 17p13.3. In the present study, a consanguineous family of Pakistani origin segregating MSSD in autosomal recessive form was characterized at clinical and genetic levels. Clinically, the diseased individuals have MSSD associated with clinodactyly and polydactyly. Homozygosity mapping followed by Sanger sequencing of BHLHA9 revealed a novel frameshift variant NM_001164405.1: c.409-409delC; p.(His137Thrfs*61) segregating with the disease phenotypes in the family. This is the second report providing evidence of association of polydactyly with MSSD caused by frameshift variant in the gene BHLHA9. The present molecular investigation will support genetic counselling of the local population carrying diseased variants.

7.
Environ Sci Pollut Res Int ; 26(7): 6745-6757, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30632035

RESUMO

Climate change adversely affects food security all over the world, especially in developing countries where the increasing population is confronting food insecurity and malnutrition. Crop models can assist stakeholders for assessment of climate change in current and future agricultural production systems. The aim of this study was to use of system analysis approach through CSM-CERES-Millet model to quantify climate change and its impact on pearl millet under arid and semi-arid climatic conditions of Punjab, Pakistan. Calibration and evaluation of CERES-Millet were performed with the field observations for pearl millet hybrid 86M86. Mid-century (2040-2069) climate change scenarios for representative concentration pathway (RCP) 4.5 and RCP 8.5 were generated based on an ensemble of selected five general circulation models (GCMs). The model was calibrated with optimum treatment (15-cm plant spacing and 200 kg N ha-1) using field observations on phenology, growth and grain yield. Thereafter, pearl millet cultivar was evaluated with remaining treatments of plant spacing and nitrogen during 2015 and 2016 in Faisalabad and Layyah. The CERES-Millet model was calibrated very well and predicted the grain yield with 1.14% error. Model valuation results showed that there was a close agreement between the observed and simulated values of grain yield with RMSE ranging from 172 to 193 kg ha-1. The results of future climate scenarios revealed that there would be an increase in Tmin (2.8 °C and 2.9 °C, respectively, for the semi-arid and arid environment) and Tmax (2.5 °C and 2.7 °C, respectively, for the semi-arid and arid environment) under RCP4.5. For RCP8.5, there would be an increase of 4 °C in Tmin for the semi-arid and arid environment and an increase of 3.7 °C and 3.9 °C in Tmax, respectively, for the semi-arid and arid environment. The impacts of climate changes showed that pearl millet yield would be reduced by 7 to 10% under RCPs 4.5 and 8.5 in Faisalabad and 10 to 13% in Layyah under RCP 4.5 and 8.5 for mid-century. So, CSM-CERES-Millet is a useful tool in assessing the climate change impacts.


Assuntos
Agricultura/estatística & dados numéricos , Mudança Climática , Monitoramento Ambiental , Milhetes/crescimento & desenvolvimento , Modelos Químicos , Clima Desértico , Grão Comestível , Paquistão , Pennisetum
9.
J Bone Miner Res ; 2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-30395363

RESUMO

Polydactyly is a common congenital anomaly of the hand and foot. Postaxial polydactyly (PAP) is characterized by one or more posterior or postaxial digits. In a Pakistani family with autosomal recessive nonsyndromic postaxial polydactyly type A (PAPA), we performed genomewide genotyping, linkage analysis, and exome and Sanger sequencing. Exome sequencing revealed a homozygous nonsense variant (c.478C>T, p.[Arg160*]) in the FAM92A gene within the mapped region on 8q21.13-q24.12 that segregated with the PAPA phenotype. We found that FAM92A is expressed in the developing mouse limb and E11.5 limb bud including the progress zone and the apical ectodermal ridge, where it strongly localizes at the cilia level, suggesting an important role in limb patterning. The identified variant leads to a loss of the FAM92A/Chibby1 complex that is crucial for ciliogenesis and impairs the recruitment and the colocalization of FAM92A with Chibby1 at the base of the cilia. In addition, we show that Fam92a-/- homozygous mice also exhibit an abnormal digit morphology, including metatarsal osteomas and polysyndactyly, in addition to distinct abnormalities on the deltoid tuberosity of their humeri. In conclusion, we present a new nonsyndromic PAPA ciliopathy due to a loss-of-function variant in FAM92A. © 2018 American Society for Bone and Mineral Research.

10.
BMC Med Genet ; 19(1): 199, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30442103

RESUMO

BACKGROUND: Mutations in the genes encoding leptin (LEP), the leptin receptor (LEPR), and the melanocortin 4 receptor (MC4R) are known to cause severe early-onset childhood obesity. The aim of the current study was to examine the prevalence of damaging LEP, LEPR, and MC4R mutations in Pakistani families having a recessive heritance of early-onset obesity. METHODS: Using targeted resequencing, the presence of rare mutations in LEP, LEPR, and MC4R, was investigated in individuals from 25 families suspected of having autosomal recessive early-onset obesity. Segregation patterns of variants were assessed based on chip-based genotyping. RESULTS: Homozygous LEPR variants were identified in two probands. One carried a deletion (c.3260AG) resulting in the frameshift mutation p.Ser1090Trpfs*6, and the second carried a substitution (c.2675C > G) resulting in the missense mutation p.Pro892Arg. Both mutations were located within regions of homozygosity shared only among affected individuals. Both probands displayed early-onset obesity, hyperphagia and diabetes. No mutations were found in LEP and MC4R. CONCLUSIONS: The current study highlights the implication of LEPR mutations in cases of severe early-onset obesity in consanguineous Pakistani families. Through targeted resequencing, we identified novel damaging mutations, and our approach may therefore be utilized in clinical testing or diagnosis of known forms of monogenic obesity with the aim of optimizing obesity treatment.

11.
PLoS One ; 13(9): e0202464, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30231071

RESUMO

Minimization functionals related to Euler's elastica energy has a broad range of applications in computer vision and image processing. This paper proposes a novel Euler's elastica and curvature-based variational model for image restoration corrupted with multiplicative noise. It combines Euler's elastica curvature with a Weberized total variation (TV) regularization and gets a novel Euler's elastica energy and TV-based minimization functional. The combined approach in this variational model can preserve edges while reducing the blocky effect in smooth regions. The implicit gradient descent scheme is applied to efficiently finding the minimizer of the proposed functional. Experimental results demonstrate the effectiveness of the proposed model in visual improvement, as well as an increase in the peak signal-to-noise ratio, compared to the PDE-based methods.

12.
Eur J Med Genet ; 2018 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-30107244

RESUMO

Mesoaxial syndactyly is characterized by fusion of the central digits. The disorder segregates in autosomal recessive pattern and mapped on human chromosome 17p13.3. Homozygous missense mutations in the BHLHA9 have been reported to cause mesoaxial synostotic syndactyly with phalangeal reduction (MSSD). In the present study, we have investigated a family segregating mesoaxial synostotic syndactyly with phalangeal reduction (MSSD) in autosomal recessive manner. Genotyping using microsatellite markers followed by Sanger sequencing revealed a homozygous deletion and insertion mutation (NM_001164405: c.252_270delinsGCA; p.(Phe85Glufs*108)) in the BHLHA9 gene in affected individuals of the family. This study reports the first frameshift mutation in the BHLHA9 causing mesoaxial synostotic syndactyly and phalangeal reduction.

13.
Environ Sci Pollut Res Int ; 25(28): 28413-28430, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30083905

RESUMO

Climate change and variability are major threats to crop productivity. Crop models are being used worldwide for decision support system for crop management under changing climatic scenarios. Two-year field experiments were conducted at the Water Management Research Center (WMRC), University of Agriculture Faisalabad, Pakistan, to evaluate the application of CERES-Maize model for climate variability assessment under semi-arid environment. Experimental treatments included four sowing dates (27 January, 16 February, 8 March, and 28 March) with three maize hybrids (Pioneer-1543, Mosanto-DK6103, Syngenta-NK8711), adopted at farmer fields in the region. Model was calibrated with each hybrid independently using data of best sowing date (27 January) during the year 2015 and then evaluated with the data of 2016 and remaining sowing dates. Performance of model was evaluated by statistical indices. Model showed reliable information with phenological stages. Model predicted days to anthesis and maturity with lower RMSE (< 2 days) during both years. Model prediction for biological yield and grain yield were reasonably good with RMSE values of 963 and 451 kg ha-1, respectively. Model was further used to assess climate variability. Historical climate data (1980-2016) were used as input to simulate the yield for each year. Results showed that days to anthesis and maturity were negatively correlated with increase in temperature and coefficient of regression ranged from 0.63 to 0.85, while its values were 0.76 to 0.89 kg ha-1 for grain yield and biological yield, respectively. Sowing of maize hybrids (Pioneer-1543 and Mosanto-DK6103) can be recommended for the sowing on 17 January to 6 February at the farmer field for general cultivation in the region. Early sowing before 17 January should be avoided due to severe reduction in grain yield of all hybrids. A good calibrated CERES-Maize model can be used in decision-making for different management practices and assessment of climate variability in the region.

14.
Hum Genet ; 137(6-7): 471-478, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29971487

RESUMO

Hereditary hearing impairment is a common sensory disorder that is genetically and phenotypically heterogeneous. In this study, we used a homozygosity mapping and exome sequencing strategy to study a consanguineous Pakistani family with autosomal recessive severe-to-profound hearing impairment. This led to the identification of a missense variant (p.Ile369Thr) in the LMX1A gene affecting a conserved residue in the C-terminus of the protein, which was predicted damaging by an in silico bioinformatics analysis. The p.Ile369Thr variant disrupts several C-terminal and homeodomain residue interactions, including an interaction with homeodomain residue p.Val241 that was previously found to be involved in autosomal dominant progressive HI. LIM-homeodomain factor Lmx1a is expressed in the inner ear through development, shows a progressive restriction to non-sensory epithelia, and is important in the separation of the sensory and non-sensory domains in the inner ear. Homozygous Lmx1a mutant mice (Dreher) are deaf with dysmorphic ears with an abnormal morphogenesis and fused and misshapen sensory organs; however, computed tomography performed on a hearing-impaired family member did not reveal any cochleovestibular malformations. Our results suggest that LMX1A is involved in both human autosomal recessive and dominant sensorineural hearing impairment.

15.
Eur J Orthop Surg Traumatol ; 28(8): 1609-1616, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29845326

RESUMO

PURPOSE: To assess the functional outcome of acute primary total hip replacement in the management of complex acetabular fractures. MATERIALS AND METHODS: This prospective observational study was conducted in orthopedic department of Liaquat National Hospital and Medical College, Karachi. The study was approved by the Ethics review committee of hospital (0190-2016). Patients who encountered between January 2010 to January 2016 were entered. Fifty-four patients with acetabular fractures with certain indications (marginal impaction or significant comminution (> 3 fragments) of the articular surface of the acetabulum, full-thickness articular injury to the femoral head, an associated femur neck fracture, or preexisting symptomatic osteoarthritis) were treated with primary total hip replacement. Patients were followed in outpatient clinic at regular intervals after discharge to assess the radiological union of fractures and complications. Functional outcome was evaluated after 2 years by applying Harris Hip Score. All statistical analysis was done by using SPSS version 20. RESULTS: All patients achieved radiological union of fractures at an average duration of 21 weeks. During the follow-up, seven complications were observed. Two patients developed superficial surgical site infection which was treated conservatively. One patient had dislocation which was reduced closely, while two patients had acetabular cup loosening which was revised. We also observed two cases of Brooker I heterotopic ossification and one case of Brooker II. At 2-year follow-up, 78% of patients had an excellent and good functional outcome according to Harris Hip score. CONCLUSION: Primary total hip replacement is a valid and reasonable one stage surgical treatment of complex acetabular fractures and in aged individuals. However, the complications are not uncommon.

16.
Genet. mol. biol ; 41(1): 1-8, Jan.-Mar. 2018. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-892477

RESUMO

Abstract Split-hand/split-foot malformation (SHFM), also known as ectrodactyly is a rare genetic disorder. It is a clinically and genetically heterogeneous group of limb malformations characterized by absence/hypoplasia and/or median cleft of hands and/or feet. To date, seven genes underlying SHFM have been identified. This study described four consanguineous families (A-D) segregating SHFM in an autosomal recessive manner. Linkage in the families was established to chromosome 12p11.1-q13.13 harboring WNT10B gene. Sequence analysis identified a novel homozygous nonsense variant (p.Gln154*) in exon 4 of the WNT10B gene in two families (A and B). In the other two families (C and D), a previously reported variant (c.300_306dupAGGGCGG; p.Leu103Argfs*53) was detected. This study further expands the spectrum of the sequence variants reported in the WNT10B gene, which result in the split hand/foot malformation.

17.
Genet Mol Biol ; 41(1): 1-8, 2018 Jan-Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29384555

RESUMO

Split-hand/split-foot malformation (SHFM), also known as ectrodactyly is a rare genetic disorder. It is a clinically and genetically heterogeneous group of limb malformations characterized by absence/hypoplasia and/or median cleft of hands and/or feet. To date, seven genes underlying SHFM have been identified. This study described four consanguineous families (A-D) segregating SHFM in an autosomal recessive manner. Linkage in the families was established to chromosome 12p11.1-q13.13 harboring WNT10B gene. Sequence analysis identified a novel homozygous nonsense variant (p.Gln154*) in exon 4 of the WNT10B gene in two families (A and B). In the other two families (C and D), a previously reported variant (c.300_306dupAGGGCGG; p.Leu103Argfs*53) was detected. This study further expands the spectrum of the sequence variants reported in the WNT10B gene, which result in the split hand/foot malformation.

19.
Ann Hum Genet ; 82(3): 129-134, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29322508

RESUMO

Acromesomelic dysplasia is genetically heterogeneous group of skeletal disorders characterized by short stature and acromelia and mesomelia of limbs. Acromesomelic dysplasia segregates in an autosomal recessive pattern and is caused by biallelic sequence variants in three genes (NPR2, GDF5, and BMPR1B). A consanguineous family of Pakistani origin segregating a subtype of acromesomelic dysplasia called Hunter-Thompson was clinically and genetically evaluated. Genotyping of microsatellite markers and linkage analysis revealed a 7.78 Mb homozygous region on chromosome 4q22.3, which harbors BMPR1B. Sequence analysis of the gene revealed a novel homozygous missense variant (c.1190T > G, p.Met397Arg) that segregates with the disease phenotype within the family and produced a Logarithm of odds (LOD) score of 3.9 with the disease phenotype. This study reports on the first familial case of acromesomelic dysplasia Hunter-Thompson type. It is also the first report of BMPR1B underlying the etiology of acromesomelic dysplasia Hunter-Thompson type.

20.
J Hum Genet ; 63(1): 97-100, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29215096

RESUMO

Frontorhiny is one of the two forms of mid-facial malformations characterized by ocular hypertelorism, wide and short nasal ridge, bifid nasal tip, broad columella, widely separated nares, long and wide philtrum and V-shaped hairline. Sometimes these phenotypes are associated with ptosis and midline dermoid cysts. Frontorhiny inherits in an autosomal recessive pattern. Sequence variants in the Aristaless-like homeobox 3 (ALX3) gene underlying frontorhiny have been reported previously. Here, in the present study, we have investigated four patients in a consanguineous family of Pakistani origin segregating frontorhiny in autosomal recessive manner. Genome scan using 250k Nsp1 array followed by exome and Sanger sequence analysis revealed a novel homozygous nonsense variant (c.604C>T, p.Gln202*) in the ALX3 gene resulting in frontorhiny in the family. This is the first mutation in the ALX3 gene, underlying frontorhiny, in Pakistani population.


Assuntos
Códon sem Sentido , Anormalidades Craniofaciais/genética , Exoma , Face/anormalidades , Proteínas de Homeodomínio/genética , Anormalidades Craniofaciais/patologia , Análise Mutacional de DNA , Face/patologia , Família , Feminino , Humanos , Masculino , Paquistão , Linhagem
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