scholarly journals Phenotypic distinctions of BLM- and RMI1-associated Bloom syndrome

2021 ◽  
Author(s):  
Ipek Ilgin Gonenc ◽  
Nursel Huriye Elcioglu ◽  
Carolina Martinez Grijalva ◽  
Seda Aras ◽  
Nadine Grossmann ◽  
...  
Keyword(s):  
Upper Airway ◽  
Skin Lesions ◽  
Bloom Syndrome ◽  
Growth Delay ◽  
Homozygous Mutation ◽  
Loss Of Function ◽  
Primary Microcephaly ◽  
Whole Exome ◽  
Airway Infections ◽  
Turkish Family

Bloom syndrome (BS) is an autosomal recessive disease with characteristic clinical features of primary microcephaly, growth deficiency, skin lesions, cancer predisposition, and immunodeficiency. Here, we report the clinical and molecular findings of eight patients from six families diagnosed with BS. We identified causative mutations in all families, three different homozygous mutations in BLM and one causative homozygous mutation in RMI1. The homozygous c.581_582delTT (p.Phe194*) and c.3164G>C (p.Cys1055Ser) mutations in BLM have already been reported in BS patients, while the c.572_573delGA (p.Arg191Lysfs*4) is novel. Interestingly, whole-exome sequencing revealed a homozygous loss-of-function mutation in RMI1 in two BS patients of a consanguineous Turkish family. All BS patients had primary microcephaly, intrauterine growth delay, and short stature, presenting the phenotypic hallmarks of BS. However, a narrow face, skin lesions, and upper airway infections were observed only in some of the patients. Overall, patients with homozygous BLM mutations had a more severe BS phenotype compared to patients carrying the homozygous RMI1 mutation, especially in terms of immunodeficiency and associated recurrent infections. Low-level immunoglobulins were observed in all BLM-mutated patients, emphasizing the immunodeficiency profile of the disease, which should be considered as an important phenotypic characteristic of BS, especially in the current Covid-19 pandemic era.

scholarly journals Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis

2019 ◽  
Vol 116 (38) ◽  
pp. 19055-19063 ◽  
Author(s):  
Scott B. Drutman ◽  
Filomeen Haerynck ◽  
Franklin L. Zhong ◽  
David Hum ◽  
Nicholas J. Hernandez ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Upper Airway ◽  
Recurrent Respiratory Papillomatosis ◽  
Human Papillomaviruses ◽  
Inflammasome Activation ◽  
Homozygous Mutation ◽  
Gain Of Function ◽  
Pyrin Domain ◽  
Whole Exome ◽  
Overexpression System

Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP following exposure to these common viruses. We report 2 siblings with a syndromic form of JRRP associated with mild dermatologic abnormalities. Whole-exome sequencing of the patients revealed a private homozygous mutation in NLRP1, encoding Nucleotide-Binding Domain Leucine-Rich Repeat Family Pyrin Domain-Containing 1. We find the NLRP1 mutant allele to be gain of function (GOF) for inflammasome activation, as demonstrated by the induction of inflammasome complex oligomerization and IL-1β secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1β at baseline. Finally, both patients displayed elevated levels of inflammasome-induced cytokines in the serum. Six NLRP1 GOF mutations have previously been described to underlie 3 allelic Mendelian diseases with differing phenotypes and modes of inheritance. Our results demonstrate that an autosomal recessive, syndromic form of JRRP can be associated with an NLRP1 GOF mutation.

A Novel Frameshift Mutation in Abnormal Spindle-Like Microcephaly (ASPM) Gene in an Iranian Patient with Primary Microcephaly: A Case Report

2020 ◽  
Author(s):  
Afsaneh BAZGIR ◽  
Mehdi AGHA GHOLIZADEH ◽  
Faezeh SARVAR ◽  
Zahra PAKZAD
Keyword(s):  
Intellectual Disability ◽  
Frameshift Mutation ◽  
Genetic Disorder ◽  
Normal Function ◽  
Molecular Testing ◽  
Homozygous Mutation ◽  
Primary Microcephaly ◽  
Iranian Patient ◽  
Whole Exome ◽  
Autosomal Recessive Primary Microcephaly

Autosomal recessive primary microcephaly (MCPH) is a rare genetic disorder, leading to the defect of neurogenic brain development. Individuals with MCPH reveal reduced head circumference and intellectual disability. Several MCPH loci have been identified from several populations. Genetic heterogeneity of this disorder represents molecular testing challenge. An 8 yr old female, born from consanguineous parents, was attended to Fardis Central Lab, Alborz, Iran. Based on the reduced circumference and intellectual disability, MCPH was diagnosed. Whole exome sequencing of the patient identified a novel homozygous frameshift mutation (c.2738dupT, p.Cys914fs) in exon 9 Abnormal Spindle-like Microcephaly )ASPM( gene. By Sanger sequencing, segregation analysis showed that both parents were heterozygous carriers for this variant. The novel frameshift mutation likely truncates the protein, resulting in loss of normal function ASPM in homozygous mutation carriers. The study might add a new pathogenic variant in mutations of the ASPM gene as a causative variant in patients with MCPH and might be helpful in genetic counseling of consanguineous families.

Webb–Dattani Syndrome: Report of a Saudi Arabian Family with a Novel Homozygous Mutation in the ARNT2 Gene

2018 ◽  
Vol 17 (02) ◽  
pp. 071-076 ◽  
Author(s):  
Nouriya Abbas Al-Sannaa ◽  
Alexander Pepler ◽  
Hind Y. Al-Abdulwahed ◽  
Sami I. Al-Majed ◽  
Rifat F. Abdi ◽  
...  
Keyword(s):  
Saudi Arabian ◽  
Autosomal Recessive Disorder ◽  
Cortical Blindness ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Homozygous Mutation ◽  
Loss Of Function ◽  
Whole Exome ◽  
Retinal Examination

AbstractWebb–Dattani syndrome (WEDAS) is an autosomal recessive disorder caused by mutation in the ARNT2 gene characterized by frontotemporal hypoplasia, globally delayed development, and pituitary and hypothalamic insufficiency. The condition is reported to be associated with consanguinity and with Saudi Arabian ancestry. Here we describe a family of three affected siblings born to healthy second cousin parents of Saudi Arabian ancestry. The children presented at 3 months of age with congenital central hypotonia and hypoventilation, central diabetes insipidus, multiple pituitary hormone deficiency, severe developmental delay, acquired microcephaly, cortical blindness with normal retinal examination, seizures, and gastroesophageal reflux. Whole exome sequencing detected a homozygous unclear variant (c.378C>T; p.G126G) in the ARNT2 gene in both the affected twins. According to splice prediction programs, this variant results in the creation of a cryptic donor splice site, possibly leading to a loss of function. These data support the role of the detected mutation in the ARNT2 gene in causing the described phenotype.

scholarly journals Single-cell transcription profiles in Bloom syndrome patients link BLM deficiency with altered condensin complex expression signatures

2021 ◽  
Author(s):  
Ipek Ilgin Gönenc ◽  
Alexander Wolff ◽  
Julia Schmidt ◽  
Arne Zibat ◽  
Christian Müller ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Cell Lines ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Bloom Syndrome ◽  
Loss Of Function ◽  
Primary Microcephaly ◽  
Transcription Profiles ◽  
Condensin Complex

AbstractBloom syndrome (BS) is an autosomal recessive disease clinically characterized by primary microcephaly, growth deficiency, immunodeficiency, and predisposition to cancer. It is mainly caused by biallelic loss-of-function mutations in the BLM gene, which encodes the BLM helicase, acting in DNA replication and repair processes. Here, we describe the gene expression profiles of three BS fibroblast cell lines harboring causative, biallelic truncating mutations obtained by single-cell (sc) transcriptome analysis. We compared the scRNA transcription profiles from three BS patient cell lines to two age-matched wild-type controls and observed specific deregulation of gene sets related to the molecular processes characteristically affected in BS, such as mitosis, chromosome segregation, cell cycle regulation, and genomic instability. We also found specific upregulation of genes of the Fanconi anemia pathway, in particular FANCM, FANCD2, and FANCI, which encode known interaction partners of BLM. The significant deregulation of genes associated with inherited forms of primary microcephaly observed in our study might explain in part the molecular pathogenesis of microcephaly in BS, one of the main clinical characteristics in patients. Finally, our data provide first evidence of a novel link between BLM dysfunction and transcriptional changes in condensin complex I and II genes. Overall, our study provides novel insights into gene expression profiles in BS on a single-cell level, linking specific genes and pathways to BLM dysfunction.

scholarly journals Novel homozygous mutation in the WWOX gene causes seizures and global developmental delay: Report and review

2018 ◽  
Vol 9 (1) ◽  
pp. 203-208 ◽  
Author(s):  
Salleh N. Ehaideb ◽  
Majed J. Al-Bu Ali ◽  
Jaafer J. Al-obaid ◽  
Kareemah M. Aljassim ◽  
Majid Alfadhel
Keyword(s):  
Developmental Delay ◽  
Fragile Site ◽  
Underlying Mechanism ◽  
Suppressor Gene ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
Homozygous Mutation ◽  
Loss Of Function ◽  
Intractable Seizures ◽  
Whole Exome

AbstractTheWWOXgene has a WW domain containing oxidoreductase, which is located at the common fragile site FRA16D at chromosome 16q23.WWOXis a tumor suppressor gene that has been associated with several types of cancer such as hepatic, breast, lung, prostate, gastric, and ovarian. Recently WWOX has been implicated in epilepsy, where studies show homozygous loss-of-function mutation lead to early-infantile epileptic encephalopathy, spinocerebellar ataxia, intractable seizures and developmental delay, and early lethal microcephaly syndrome with epilepsy. Here we investigate two consanguineous Saudi families and we identified three probands with epileptic encephalopathy. Whole exome sequencing revealed a novel homozygous mutation in theWWOXgene in one proband. In addition, we identified a previously reportedWWOXmutation in two probands. Later on these findings were confirmed with Sanger sequencing. The underlying mechanism on how WWOX mutations lead to seizure remains elusive. To date very fewWWOXmutations have been associated with neurological disorder and our newly identified mutations support the notion that WWOX play an important role in neurons and will aid in better diagnosis and genetic counseling.

Hyper Immunoglobulin E Syndrome (HIES): Report of a New Case Treated with Omalizumab and Dexametasone

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4934-4934
Author(s):  
Luis Fernando Cortázar-Benítez ◽  
R.M. Rojas Sotelo ◽  
Pablo Vargas-Viveros ◽  
Rafael Hurtado-Monroy ◽  
Catalina Romo Aguirre ◽  
...  
Keyword(s):  
Immunoglobulin E ◽  
Conflicts Of Interest ◽  
Upper Airway ◽  
Severe Case ◽  
Skin Lesions ◽  
High Serum ◽  
Response To Treatment ◽  
Rapid Improvement ◽  
Serum Ige ◽  
Airway Infections

Abstract Abstract 4934 The classical triad of eczema, recurrent skin and lung infections and high serum IgE, other connective tissue, cardiac and brain abnormalities are the accepted diagnostic criteria for HIES. The treatment of HIES is not established due to the scarce number of published cases, however is limited to skin local measures and supportive care. Herein we inform a severe case with response to Omalizumab, a monoclonal anti IgE antibody in combination with Dexametasone. A 36 year old male with family history of asthma and atopic dermatitis (AD). Since child, the patient had allergies and AD. At 8 years he presented asthma and recurrent upper airway infections at 2 to 3 times per year and 7 dental pieces removal. In the last 3 years he noted important increase of AD with very intense and disabling pruritus without response to treatment and progression to generalized erithrodermia, nodes in legs and arms, and skin trasudate, axilar and inguinal lymph nodes (6×4 cm). Laboratory positive test were eosinophils 6%, serum IgE 29,280 IU/mL. Skin biopsy showed psoriasis-like dermatitis, micro abscesses and dermatopathic lymphadenopathy. We started treatment with trimetoprim/Sulfamethoxazole 80/400 mg twice a day, oral Dexametasone 20 mg weekly and Omalizumab 200 mg subcutaneously every two weeks. After 15 days of treatment there was a rapid improvement of skin derangement and IgE levels dropped to 2000 IU/mL after 16 weeks of treatment. Patient continues on treatment with no side effects and pruritus disappears. Omalizumab is a monoclonal antibody against IgE recently introduced to the treatment of HIES in a few patients reported since 2008 with excellent response, along with intensive care of skin lesions, prompt antibiotic and antimycotic treatment for infections are the mainstay of HIES management. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Whole-exome sequencing identifies homozygous mutation in TTI2 in a child with primary microcephaly: a case report

BMC Neurology ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Vincent Picher-Martel ◽  
Yvan Labrie ◽  
Serge Rivest ◽  
Baiba Lace ◽  
Nicolas Chrestian
Keyword(s):  
Case Report ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Homozygous Mutation ◽  
Primary Microcephaly ◽  
Whole Exome

Kindler's Syndrome with Recurrent Neutropenia: Report of Two Cases from Saudi Arabia

2020 ◽  
Author(s):  
Yousef Binamer ◽  
Muzamil A. Chisti
Keyword(s):  
Autosomal Recessive ◽  
Common Mechanism ◽  
Sequencing Analysis ◽  
Loss Of Function ◽  
Skin Atrophy ◽  
Whole Exome ◽  
Infancy And Childhood ◽  
Genetics And Genomics ◽  
New Feature ◽  
Generation Sequencing

AbstractKindler syndrome (KS) is a rare photosensitivity disorder with autosomal recessive mode of inheritance. It is characterized by acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. Besides these major features, many minor presentations have also been reported in the literature. We are reporting two cases with atypical features of the syndrome and a new feature of recurrent neutropenia. Whole exome sequencing analysis was done using next-generation sequencing which detected a homozygous loss-of-function (LOF) variant of FERMT1 in both patients. The variant is classified as a pathogenic variant as per the American College of Medical Genetics and Genomics guidelines. Homozygous LOF variants of FERMT1 are a common mechanism of KS and as such confirm the diagnosis of KS in our patients even though the presentation was atypical.

Autosomal Recessive Non-syndromic Keratoconus: Homozygous Frameshift Variant in the Candidate Novel Gene GALNT14

2019 ◽  
Vol 19 (9) ◽  
pp. 683-687 ◽  
Author(s):  
Tawfiq Froukh ◽  
Ammar Hawwari
Keyword(s):  
Strong Evidence ◽  
Autosomal Recessive ◽  
Eye Diseases ◽  
Initial Reaction ◽  
Genetic Contribution ◽  
Loss Of Function ◽  
Consanguineous Family ◽  
Truncated Protein ◽  
Threonine Residue ◽  
Whole Exome

Background: Keratoconus (KC) is usually bilateral, noninflammatory progressive corneal ectasia in which the cornea becomes progressively thin and conical. Despite the strong evidence of genetic contribution in KC, the etiology of KC is not understood in most cases. Methods: In this study, we used whole-exome sequencing to identify the genetic cause of KC in two sibs in a consanguineous family. The Homozygous frameshift variant NM_001253826.1:c.60delC;p.Leu21Cysfs*6 was identified in the gene Nacetylgalactosaminyltransferase 14 (GALNT14). The variant does not exist in all public databases neither in our internal exome database. Moreover, no database harbours homozygous loss of function variants in the candidate gene. Result: GALNT14 catalyses the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D- galactosamine residue to a serine or threonine residue on target proteins especially Mucins. Conclusion: As alterations of mucin’s glycosylation are linked to a number of eye diseases, we demonstrate in this study an association between the truncated protein GALNT14 and KC.

scholarly journals Identification of a novel homozygous loss-of-function mutation in FUCA1 gene causing severe fucosidosis: A case report

2021 ◽  
Vol 49 (4) ◽  
pp. 030006052110059
Author(s):  
Xinwen Zhang ◽  
Shaozhi Zhao ◽  
Hongwei Liu ◽  
Xiaoyan Wang ◽  
Xiaolei Wang ◽  
...  
Keyword(s):  
Amino Acids ◽  
Lysosomal Storage Disorder ◽  
Autosomal Recessive ◽  
Signs And Symptoms ◽  
Lysosomal Storage ◽  
Loss Of Function ◽  
Wild Type ◽  
Single Nucleotide ◽  
Whole Exome ◽  
Exon 1

Fucosidosis is a rare lysosomal storage disorder characterized by deficiency of α-L-fucosidase with an autosomal recessive mode of inheritance. Here, we describe a 4-year-old Chinese boy with signs and symptoms of fucosidosis but his parents were phenotypically normal. Whole exome sequencing (WES) identified a novel homozygous single nucleotide deletion (c.82delG) in the exon 1 of the FUCA1 gene. This mutation will lead to a frameshift which will result in the formation of a truncated FUCA1 protein (p.Val28Cysfs*105) of 132 amino acids approximately one-third the size of the wild type FUCA1 protein (466 amino acids). Both parents were carrying the mutation in a heterozygous state. This study expands the mutational spectrum of the FUCA1 gene associated with fucosidosis and emphasises the benefits of WES for accurate and timely clinical diagnosis of this rare disease.

Sign in / Sign up

Export Citation Format

Share Document