scholarly journals Variants in the PNPLA1 Gene in Families with Autosomal Recessive Congenital Ichthyosis Reveal Clinical Significance

2021 ◽  
pp. 1-11
Author(s):  
Farooq Ahmad ◽  
Ishtiaq Ahmed ◽  
Qamre Alam ◽  
Tanveer Ahmad ◽  
Ammara Khan ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Autosomal Recessive ◽  
Genetic Disorders ◽  
Genetic Diagnosis ◽  
Missense Variant ◽  
Sequence Variant ◽  
Phenotype Correlation ◽  
Congenital Ichthyosis ◽  
Whole Exome ◽  
Autosomal Recessive Congenital Ichthyosis

The term autosomal recessive congenital ichthyosis (ARCI) is the subgroup of ichthyosis, which describes a highly heterogeneous group of genetic disorders of the skin characterized by cornification and defective keratinocytes differentiation associated with mutations in at least 14 genes including <i>PNPLA1</i>. To study the molecular basis of the Pakistani kindreds (A and B) affected by ARCI, whole-exome sequencing (WES) in the DNA samples of affected members was performed followed by Sanger sequencing of the candidate gene to hunt down the disease-causing sequence variant/s. WES data analysis led to the identification of a novel nonsense sequence variant (c.892C&#x3e;T; p.Arg298*, family A) and a recurrent missense variant (c.102C&#x3e;A; p.Asp34Glu, family B) in <i>PNPLA1</i> mapped to the ARCI locus in chromosome 6p21.31. Validation and cosegregation analysis of the variants in the remaining family members of the respective families were confirmed by Sanger sequencing. The current investigation expands the spectrum of <i>PNPLA1</i> mutations and helps establish the proper clinico-genetic diagnosis and correct genotype-phenotype correlation.

scholarly journals Expanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilis—Like Autosomal Recessive Congenital Ichthyosis

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258777
Author(s):  
Cherine Charfeddine ◽  
Nadia Laroussi ◽  
Rahma Mkaouar ◽  
Raja Jouini ◽  
Olfa Khayat ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Mutational Analysis ◽  
Clinical Phenotype ◽  
Homozygous Mutation ◽  
Congenital Ichthyosis ◽  
Whole Exome ◽  
Genes Encoding ◽  
Autosomal Recessive Congenital Ichthyosis ◽  
Connexin Genes ◽  
Disorder Of Cornification

Erythrokeratodermia variabilis (EKV) is a rare disorder of cornification usually associated with dominant mutations in the GJB3 and GJB4 genes encoding connexins (Cx)31 and 30.3. Genetic heterogeneity of EKV has already been suggested. We investigated at the clinical and genetic level a consanguineous Tunisian family with 2 sisters presenting an autosomal recessive form of EKV to better characterize this disease. Mutational analysis initially screened the connexin genes and Whole-exome sequencing (WES) was performed to identify the molecular aetiology of the particular EKV phenotype in the proband. Migratory shaped erythematous areas are the initial presenting sign followed by relatively stable hyperkeratotic plaques are the two predominates characteristics in both patients. However, remarkable variability of morphological and dominating features of the disease were observed between patients. In particular, the younger sister (proband) exhibited ichthyosiform-like appearance suggesting Autosomal Recessive Congenital Ichthyosis (ARCI) condition. No causative mutations were detected in the GJB3 and GJB4 genes. WES results revealed a novel missense homozygous mutation in NIPAL4 gene (c.835C>G, p.Pro279Ala) in both patients. This variant is predicted to be likely pathogenic. In addition, in silico analysis of the mutated 3D domain structure predicted that this variant would result in NIPA4 protein destabilization and Mg2+ transport perturbation, pointing out the potential role of NIPAL4 gene in the development and maintenance of the barrier function of the epidermis. Taken togheter, these results expand the clinical phenotype associated with NIPAL4 mutation and reinforce our hypothesis of NIPAL4 as the main candidate gene for the EKV-like ARCI phenotype.

3-M syndrome – a primordial short stature disorder with novel CUL7 mutation in two Indian patients

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Radha Rama Devi Akella
Keyword(s):  
Short Stature ◽  
Autosomal Recessive ◽  
Genetic Diagnosis ◽  
Autosomal Recessive Disorder ◽  
Missense Variant ◽  
Postnatal Growth ◽  
Compound Heterozygous ◽  
Case Presentation ◽  
Whole Exome ◽  
Heterozygous Variant

Abstract Objective To evaluate the cause of short stature in children. Case presentation Two children with suspected skeletal dysplasia and short stature were evaluated. Conclusions The 3-M syndrome is a primordial growth disorder manifesting severe postnatal growth restriction, skeletal anomalies and prominent fleshy heels. The 3-M syndrome is a genetically heterogeneous disorder and the phenotype is similar. This is a rare autosomal recessive disorder with normal intellect. Two affected children have been identified by whole-exome sequencing. One patient harboured a compound heterozygous variant and the other was a homozygous missense variant. The genetic diagnosis helped in counselling the families and facilitated prenatal diagnosis in one (case 1) family.

scholarly journals Whole Exome Sequencing Revealed a Novel Sequence Variant in The OTULIN Underlying Auto-Inflammatory Syndrome

2021 ◽  
Author(s):  
Rubab Raza ◽  
Raul Jimenez-Heredia ◽  
Muhammad Zeeshan Anwar ◽  
Asmat Ullah ◽  
Ayisha Zia ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
In Silico ◽  
Sanger Sequencing ◽  
Inflammatory Diseases ◽  
Missense Variant ◽  
Sequence Variant ◽  
Whole Exome ◽  
Inflammatory Syndrome

Abstract Purpose Systemic auto-inflammatory diseases are a diverse group of heterogeneous disorders resulting in development of the systemic inflammation in absence of the inflammatory induction. Sequence variants in the OTULIN gene, which disrupts its ubiquitination activity lead to auto-inflammation, panniculitis, and dermatosis syndrome. To date, only few disease-causing variants in the OTULIN have been reported.In the study, presented here, sequence analysis of the OTULIN gene in a patient, exhibiting features of OTULIN-related auto-inflammatory syndrome (ORAS), revealed a novel disease-causing missense variant p.(Thr312Met). Further, effect of the variant on structure and function of the OTULIN protein has been examined using in silico OTULINWT and OTULINT312M. Methods Cells, collected from the patient blood, were examined by flow cytometry. Search for the disease-causing variants was carried out using exome followed by Sanger sequencing. Effect of the sequence variant on structure of the mutated protein was studied using in-silico analyses. Results Flow cytometry analysis revealed slightly reduced number of lymphocytes, marked leukocytosis, and mildly increased levels of IgG. Whole exome sequencing coupled with Sanger sequencing revealed a homozygous missense variant [c.935C>T; p.(Thr312Met)] in the OTULIN gene. In-silico analyses revealed that the missense variant reduces OTULIN’s expression and promotes accumulation of LUBAC-linked UB chains leading to auto-inflammation.Conclusion Taken together, OTULIN may act as a novel therapeutic target for the development of immunomodulatory drugs that may potentially increase or stabilize their expression. Targeting more components of the Ub-proteasome pathway may provide new opportunities for therapeutic exploitation and drug discovery.

scholarly journals Clinical and genetic investigation of ichthyosis in familial and sporadic cases in south of Tunisia: genotype–phenotype correlation

2022 ◽  
Vol 15 (1) ◽  
Author(s):  
Mariem Ennouri ◽  
Andreas D. Zimmer ◽  
Emna Bahloul ◽  
Rim Chaabouni ◽  
Slaheddine Marrakchi ◽  
...  
Keyword(s):  
Genetic Background ◽  
Autosomal Recessive ◽  
Phenotype Correlation ◽  
Genetic Investigation ◽  
Congenital Ichthyosis ◽  
Genotype Phenotype Correlation ◽  
Tunisian Patients ◽  
Autosomal Recessive Congenital Ichthyosis ◽  
Sporadic Cases ◽  
Ichthyosis Linearis Circumflexa

Abstract Background Ichthyosis is a heterogeneous group of Mendelian cornification disorders that includes syndromic and non-syndromic forms. Autosomal Recessive Congenital Ichthyosis (ARCI) and Ichthyosis Linearis Circumflexa (ILC) belong to non-syndromic forms. Syndromic ichthyosis is rather a large group of heterogeneous diseases. Overlapping phenotypes and genotypes between these disorders is a major characteristic. Therefore, determining the specific genetic background for each form would be necessary. Methods A total of 11 Tunisian patients with non-syndromic (8 with ARCI and 2 with ILC) and autosomal syndromic ichthyosis (1 patient) were screened by a custom Agilent HaloPlex multi-gene panel and the segregation of causative mutations were analyzed in available family members. Results Clinical and molecular characterization, leading to genotype–phenotype correlation in 11 Tunisian patients was carried out. Overall, we identified 8 mutations in 5 genes. Thus, in patients with ARCI, we identified a novel (c.118T > C in NIPAL4) and 4 already reported mutations (c.534A > C in NIPAL4; c.788G > A and c.1042C > T in TGM1 and c.844C > T in CYP4F22). Yellowish severe keratoderma was found to be associated with NIPAL4 variations and brachydactyly to TGM1 mutations. Two novel variations (c.5898G > C and c.2855A > G in ABCA12) seemed to be features of ILC. Delexon13 in CERS3 was reported in a patient with syndromic ichthyosis. Conclusions Our study further extends the spectrum of mutations involved in ichthyosis as well as clinical features that could help directing genetic investigation.

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