Greig Cephalopolysyndactyly Syndrome: Phenotypic Variability Associated with Variants in Two Different Domains of GLI3

2020 ◽  
Author(s):  
Hammal Khan ◽  
Sohail Ahmed ◽  
Sadia Nawaz ◽  
Wasim Ahmad ◽  
Muhammad Arshad Rafiq ◽  
...  
Keyword(s):  
Skeletal Development ◽  
Phenotypic Variability ◽  
Transcriptional Regulator ◽  
Molecular Study ◽  
Inherited Disorders ◽  
Pakistani Population ◽  
Greig Cephalopolysyndactyly Syndrome ◽  
Novel Variants ◽  
Limb Malformations ◽  
Pleiotropic Gene

Abstract Background GLI3 is a transcriptional regulator of several genes involved in mammalian skeletal development. Mutations in the pleiotropic gene GLI3 may result in different inherited disorders including Greig cephalopolysyndactyly syndrome (GCPS). GCPS is characterized by mild to severe craniofacial and limb malformations. Methods and Results Here, we report clinical and molecular study of 3 families with GCPS originated in different regions of Pakistan. Sanger sequencing revealed two novel variants including a frameshift [c. 3790_3791InsC, p.(Gly1236Argfs*11)] and a missense [c.1692A>G, p.(His536Arg)], and one previously reported variant [c.1965_1966delAT, p.(His627Glufs*48)] located in 2 different domains of the GLI3. Conclusion This study not only expanded spectrum of the mutations in the GLI3 but also highlighted phenotypic variability in the GCPS patients. This will facilitate diagnosis and genetic counseling of families with same and related disorders in the Pakistani population.

Molecular Analysis of the CYP11B2 Gene in 62 Patients with Hypoaldosteronism Due to Aldosterone Synthase Deficiency

2020 ◽  
Vol 106 (1) ◽  
pp. e182-e191
Author(s):  
Christina Merakou ◽  
Irene Fylaktou ◽  
Amalia Sertedaki ◽  
Maria Dracopoulou ◽  
Antonis Voutetakis ◽  
...  
Keyword(s):  
Gene Sequencing ◽  
Failure To Thrive ◽  
In Silico Analysis ◽  
Autosomal Recessive Disorder ◽  
Molecular Study ◽  
Aldosterone Synthase ◽  
Salt Wasting ◽  
Pathogenic Variants ◽  
Novel Variants ◽  
Aldosterone Synthase Deficiency

Abstract Context Isolated congenital hypoaldosteronism presents in early infancy with symptoms including vomiting, severe dehydration, salt wasting, and failure to thrive. The main causes of this rare autosomal recessive disorder is pathogenic variants of the CYP11B2 gene leading to aldosterone synthase deficiency. Objective To investigate the presence of CYP11B2 pathogenic variants in a cohort of patients with a clinical, biochemical, and hormonal profile suggestive of aldosterone synthase deficiency. Design Clinical and molecular study. Setting Tertiary academic Children’s Hospital, Center for Rare Pediatric Endocrine Diseases. Patients and Methods Sixty-two patients (56 unrelated patients and 6 siblings), with hypoaldosteronism and their parents, underwent CYP11B2 gene sequencing after its selective amplification against the highly homologous CYP11B1 gene. In silico analysis of the identified novel variants was carried out to evaluate protein stability and potential pathogenicity. Results CYP11B2 gene sequencing revealed that 62 patients carried a total of 12 different pathogenic CYP11B2 gene variants, 6 of which are novel. Importantly, 96% of the 56 patients carried the previously reported p.T185I variant either in homozygosity or in compound heterozygosity with another variant. The 6 novel variants detected were: p.M1I, p.V129M, p.R141Q, p.A165T, p.R448C, and the donor splice site variant of intron 8, c.1398 + 1G > A. Conclusion Molecular diagnosis was achieved in 62 patients with aldosterone synthase deficiency, the largest cohort thus far reported. Six novel genetic variants were identified as possibly pathogenic, extending the spectrum of reported molecular defects of the CYP11B2 gene.

Mitochondrial Disorders of DNA Polymerase γ Dysfunction: From Anatomic to Molecular Pathology Diagnosis

2011 ◽  
Vol 135 (7) ◽  
pp. 925-934
Author(s):  
Linsheng Zhang ◽  
Sherine S. L. Chan ◽  
Daynna J. Wolff
Keyword(s):  
Dna Polymerase ◽  
Molecular Mechanisms ◽  
Clinical Laboratory ◽  
Laboratory Diagnosis ◽  
Molecular Study ◽  
Mitochondrial Disorders ◽  
Definitive Diagnosis ◽  
Inherited Disorders ◽  
Cooperative Effort ◽  
Dna Polymerase Γ

Abstract Context.—Primary mitochondrial dysfunction is one of the most common causes of inherited disorders predominantly involving the neuromuscular system. Advances in the molecular study of mitochondrial DNA have changed our vision and our approach to primary mitochondrial disorders. Many of the mitochondrial disorders are caused by mutations in nuclear genes and are inherited in an autosomal recessive pattern. Among the autosomal inherited mitochondrial disorders, those related to DNA polymerase γ dysfunction are the most common and the best studied. Understanding the molecular mechanisms and being familiar with the recent advances in laboratory diagnosis of this group of mitochondrial disorders are essential for pathologists to interpret abnormal histopathology and laboratory results and to suggest further studies for a definitive diagnosis. Objectives.—To help pathologists better understand the common clinical syndromes originating from mutations in DNA polymerase γ and its associated proteins and use the stepwise approach of clinical, laboratory, and pathologic diagnosis of these syndromes. Data Sources.—Review of pertinent published literature and relevant Internet databases. Conclusions.—Mitochondrial disorders are now better recognized with the development of molecular tests for clinical diagnosis. A cooperative effort among primary physicians, diagnostic pathologists, geneticists, and molecular biologists with expertise in mitochondrial disorders is required to reach a definitive diagnosis.

G.P.11.13 Molecular study of a Mexican family with PMP22 duplication with great phenotypic variability

2007 ◽  
Vol 17 (9-10) ◽  
pp. 826
Author(s):  
M. Arenas-Sordo ◽  
E. Hernández-Zamora ◽  
R. Gómez-Ortega ◽  
M. Valdés-Flores ◽  
M. Castillo-Herrera ◽  
...  
Keyword(s):  
Phenotypic Variability ◽  
Molecular Study ◽  
Mexican Family ◽  
Pmp22 Duplication

scholarly journals First Report of Two Egyptian Patients with Desbuquois Dysplasia due to Homozygous CANT1 Mutations

2021 ◽  
pp. 1-10
Author(s):  
Manal M. Thomas ◽  
Engy A. Ashaat ◽  
Ghada A. Otaify ◽  
Samira Ismail ◽  
Mona L. Essawi ◽  
...  
Keyword(s):  
Short Stature ◽  
Phenotypic Variability ◽  
Gene Mutations ◽  
Molecular Study ◽  
Phenotypic Spectrum ◽  
Desbuquois Dysplasia ◽  
Whole Exome ◽  
Egyptian Patients ◽  
Characteristic Features

Desbuquois dysplasia type 1 (DBQD1) is a very rare skeletal dysplasia characterized by growth retardation, short stature, distinct hand features, and a characteristic radiological monkey wrench appearance at the proximal femur. We report on 2unrelated Egyptian patients having the characteristic features of DBQD1 with different expressivity. Patient 1 presented at the age of 45 days with respiratory distress, short limbs, faltering growth, and distinctive facies while patient 2 presented at 5 years of age with short stature and hypospadias. The 2 patients shared radiological features suggestive of DBQD1. Whole-exome sequencing revealed a homozygous frameshift mutation in the <i>CANT1</i> gene (NM_001159772.1:c.277_278delCT; p.Leu93ValfsTer89) in patient 1 and a homozygous missense mutation (NM_138793.4:c.898C&#x3e;T; p.Arg300Cys) in patient 2. Phenotypic variability and variable expressivity of DBQD was evident in our patients. Hypoplastic scrotum and hypospadias were additional unreported associated findings, thus expanding the phenotypic spectrum of the disorder. We reviewed the main features of skeletal dysplasias exhibiting similar radiological manifestations for differential diagnosis. We suggest that the variable severity in both patients could be due to the nature of the <i>CANT1</i> gene mutations which necessitates the molecular study of more cases for phenotype-genotype correlations.

scholarly journals PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families

2021 ◽  
Author(s):  
Anne Guimier ◽  
Melanie T. Achleitner ◽  
Anne Moreau de Bellaing ◽  
Matthew Edwards ◽  
Loïc de Pontual ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Arrest ◽  
Sudden Cardiac Death ◽  
Cardiac Death ◽  
Alcohol Intake ◽  
Phenotypic Variability ◽  
Sudden Cardiac Arrest ◽  
Molecular Data ◽  
Inorganic Pyrophosphatase ◽  
Novel Variants

Abstract Purpose Biallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants. Methods Synthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized. Results Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure. One case was diagnosed prenatally with cardiomyopathy. Four teenagers drank alcohol before sudden cardiac arrest. Progressive neurological signs were observed in 2/6 surviving individuals. For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity. Conclusion We expand the clinical and mutational spectrum associated with PPA2 dysfunction. Heart failure and sudden cardiac arrest occur at various ages with inter- and intrafamilial phenotypic variability, and presentation can include progressive neurological disease. Alcohol intake can trigger cardiac arrest and should be strictly avoided.

scholarly journals Phenotypic variability of CLDN14 mutations causing DFNB29 hearing loss in the Pakistani population

2012 ◽  
Vol 58 (2) ◽  
pp. 102-108 ◽  
Author(s):  
Zil-e-Huma Bashir ◽  
Noreen Latief ◽  
Inna A Belyantseva ◽  
Farheena Iqbal ◽  
Sheikh Amer Riazuddin ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Phenotypic Variability ◽  
Pakistani Population

Novel Variants and Clinical Characteristics of 16 Patients from Southeast Asia with Genetic Variants in Neurofibromin-1

2021 ◽  
Author(s):  
Grace Lin ◽  
Heming Wei ◽  
Angeline H. M. Lai ◽  
Ee-Shien Tan ◽  
Jiin Ying Lim ◽  
...  
Keyword(s):  
Diagnostic Criteria ◽  
Splice Variants ◽  
Clinical Manifestations ◽  
Neurofibromatosis Type ◽  
Inherited Disorders ◽  
Targeted Next Generation Sequencing ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Novel Variants ◽  
Neurofibromin 1

AbstractNeurofibromatosis type 1 (NF1) is one of the most common inherited disorders. It is caused by mutations in the neurofibromin-1 gene (NF1) and affects the formation and growth of nerve tissues. More than 3,600 pathogenic variants in the NF1 gene have been identified from patients with most of the germline variants are from the Western populations. We found 16 patients (15 Chinese and 1 Asian Indian) who had heterozygous variants in NF1 through targeted next-generation sequencing. There were 15 different variants: 4 frameshift, 4 nonsense, 5 missense, and 2 splice variants. One nonsense variant and three frameshift variants had never been reported in any population or patient database. Twelve of the 16 patients met the NF1 diagnostic criteria, and each was found to have a pathogenic or likely pathogenic variant. Three different missense variants of unknown significance were discovered in the other four patients who did not meet NF1 diagnostic criteria. Our findings add four novel variants to the list of genetic mutations linked to NF1's various clinical manifestations.

scholarly journals Erratum: Phenotypic variability of CLDN14 mutations causing DFNB29 hearing loss in the Pakistani population

2013 ◽  
Vol 58 (9) ◽  
pp. 641-641
Author(s):  
Zil-e-Huma Bashir ◽  
Noreen Latief ◽  
Inna A Belyantseva ◽  
Farheena Iqbal ◽  
Sheikh Amer Riazuddin ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Phenotypic Variability ◽  
Pakistani Population

Novel Variants of RPGR in X-Linked Retinitis Pigmentosa Families and Genotype-Phenotype Correlation

2016 ◽  
Vol 27 (2) ◽  
pp. 240-248 ◽  
Author(s):  
Francesco Parmeggiani ◽  
Vanessa Barbaro ◽  
Angelo Migliorati ◽  
Paolo Raffa ◽  
Patrizia Nespeca ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Genetic Variants ◽  
Novel Mutation ◽  
Phenotypic Variability ◽  
Open Reading Frames ◽  
Pathological Effect ◽  
Exon 2 ◽  
Novel Variants ◽  
Ophthalmologic Examination ◽  
Exon 10

Purpose To identify novel mutations in the retinitis pigmentosa GTPase regulator ( RPGR) gene and retinitis pigmentosa 2 ( RP2) gene underlying X-linked retinitis pigmentosa (XLRP) and assess genotype-phenotype correlations. Methods The patient cohort, consisting of 13 individuals from 3 unrelated XLRP families, underwent comprehensive ophthalmologic examination. The open reading frames of RPGR and RP2 were analyzed with Sanger sequencing in each patient. The identified genetic variants were defined as mutations or polymorphisms on the basis of their pathological effect. Results We found 3 genetic variants: a novel mutation c.1591G>T in exon 14 and a novel polymorphism c.1105C>T in exon 10, resulting in p.Glu531* and p.Arg369Cys of RPGR gene, respectively, and one already known mutation c.413A>G in exon 2, resulting in a p.Glu138Gly of RP2 gene. Considering our XLRP probands, RPGR-related phenotypic damages were similar and less severe than those of the patient with the RP2 mutation. On the other hand, the female carriers of XLRP variants showed different RPGR-related consequences, ranging from rods hypofunctionality in c.1591G>T nonsense heterozygosity to no retinal changes in c.1105C>T polymorphic heterozygosity. Conclusions These findings broaden the spectrum of RPGR mutations and phenotypic variability of the disease, which will be useful for genetic consultation and diagnosis in the future.

scholarly journals A Frameshift Variant in KIAA0825 Causes Postaxial Polydactyly

2020 ◽  
pp. 1-5
Author(s):  
Muhammad Bilal ◽  
Wasim Ahmad
Keyword(s):  
Stop Codon ◽  
Premature Stop Codon ◽  
Causative Gene ◽  
Pakistani Population ◽  
Postaxial Polydactyly ◽  
The Family ◽  
Novel Variant ◽  
Limb Malformations ◽  
Polymorphic Microsatellite ◽  
Autosomal Recessive Manner

Postaxial polydactyly (PAP) is characterized by counterproductive 5th digit (pinky finger) duplication on hands and/or feet which often leads to functional complications. To date, at least 11 genes involved in causing various types of nonsyndromic polydactylies have been reported. In the present study, a consanguineous family of Sindhi origin with a segregating nonsyndromic form of PAP in an autosomal recessive manner was clinically and genetically evaluated. Genotyping, using polymorphic microsatellite markers, established linkage in the family on chromosome 5q15 harboring the <i>KIAA0825</i> gene (MIM 617266). Sequence analysis of the gene revealed a novel frameshift variant leading to a premature stop codon [c.143delG, p.(Cys48Serfs*28)]. This is only the 4th novel variant in the <i>KIAA0825</i> gene that leads to PAP type A10 (PAPA10) (MIM 618498). Identification of variants in the PAP causative gene will support the diagnosis of patients with limb malformations in the Pakistani population.

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