Occurrence of Esophageal Atresia With Tracheoesophageal Fistula in Siblings From Three-Generation Family Affected by Variable Expressivity MYCN Mutation: A Case Report

The MYCN oncogene encodes a transcription factor belonging to the MYC family. It is primarily expressed in normal developing embryos and is thought to be critical in brain and other neural development. Loss-of-function variants resulting in haploinsufficiency of MYCN, which encodes a protein with a basic helix–loop–helix domain causes Feingold syndrome (OMIM 164280, ORPHA 391641). We present an occurrence of esophageal atresia (EA) with tracheoesophageal fistula in siblings from a three-generation family affected by variable expressivity of MYCN mutation p.(Ser90GlnfsTer176) as a diagnostic effect of searching the cause of familial esophageal atresia using NGS-based whole-exome sequencing (WES). All of our affected patients showed microcephaly and toe syndactyly, which were frequently reported in the literature. Just one patient exhibited clinodactyly. None of the patients exhibited brachymesophalangy or hypoplastic thumbs. The latest report noted that patients with EA and Feingold syndrome were also those with the more complex and severe phenotype. However, following a thorough review of the present literature, the same association was not found, which is also confirmed by the case we described. The variable phenotypic expression of the patients we described and the data from the literature guide a careful differential diagnosis of Feingold syndrome even in cases of poorly expressed and non-specific symptoms.

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Sa2011 - Novel Candidate Genes in Esophageal Atresia/Tracheoesophageal Fistula Identified by Whole Exome Sequencing

Gastroenterology ◽

10.1016/s0016-5085(18)31747-5 ◽

2018 ◽

Vol 154 (6) ◽

pp. S-446-S-447

Author(s):

Julie Khlevner ◽

William Middlesworth ◽

Jiayao Wang ◽

Priyanka R. Ahimaz ◽

Jianwen Que ◽

...

Keyword(s):

Exome Sequencing ◽

Candidate Genes ◽

Whole Exome Sequencing ◽

Esophageal Atresia ◽

Tracheoesophageal Fistula ◽

Whole Exome

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

Journal of Pediatric Genetics ◽

10.1055/s-0040-1721077 ◽

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.

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

Current Molecular Medicine ◽

10.2174/1566524019666190730095630 ◽

2019 ◽

Vol 19 (9) ◽

pp. 683-687 ◽

Cited By ~ 3

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.

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

Journal of International Medical Research ◽

10.1177/03000605211005975 ◽

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.

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AB0994 NEW ALTERNATIVE IN THE TREATMENT OF PATIENT WITH MUTATION OF GEN LACC1

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5555 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1790.2-1790

Author(s):

R. M. Alcobendas ◽

C. Quintana ◽

J. Arostegui ◽

C. Udaondo ◽

S. Murias Loza ◽

...

Keyword(s):

Chart Review ◽

Loss Of Function ◽

Acute Phase Reactants ◽

Reactive Protein ◽

Inflammatory Parameters ◽

Whole Exome ◽

Multiple Treatments ◽

Clinical Chart ◽

Clinical Worsening

Background:Few patients have been described in the literature with mutations in the Lacasa Domain containing one (LACC1) gene. Its clinical presentation usually associates sustained systemic inflammation associated with chronic polyarticular erosive arthritis. Until now, there have been multiple treatments described to try to control the disease, however, they are generally unsuccessful in the long term.Objectives:Describe the clinical course of a patient as well as the different treatments usedMethods:Clinical chart reviewResults:Female 18-year-old born from a consanguineous Moroccan couple. Mother, brother and sister with similar conditions. She started at 3 years with fever, anemia, intense elevation of acute phase reactants and symmetric polyarthritis (knees, elbows, carps, shoulders, hands and ankles). Subsequent whole exome sequencing identified c.128_129delGT mutation in the LACC1/FAMIN gene. During the course of her illness, she has received treatment with oral, intravenous and infiltrated corticosteroid, methotrexate and etanercept, without getting adequate control of the disease. In 2016, she started treatment with tocilizumab (8 mg / kg every two weeks), obtaining an acceptable control of the disease (requiring periodic infiltrations every 2-3 months due to persistent arthritis). Nonetheless, in April 2019, she consulted for clinical worsening of the arthritis and laboratory test (C reactive protein 99.7 mg / L, erythrosedimentation rate 53 mm / h, leukocytes 13,500/µL and neutrophils 10,930/µL). At that time, she discontinued therapy with tocilizumab and started tofacitinib 5 mg every 12 hours with good evolution. Since its introduction, it has not required joint infiltration again and the inflammatory parameters (persistently elevated previously) have normalized.Conclusion:The jak kinasa inhibitors may be a treatment option in those patients with bad response to conventional therapy.References:[1]Rabionet R, Remesal A, Mensa-Vilaró A, Murías S, Alcobendas R, González-Roca E, Ruiz-Ortiz E, Antón J, Iglesias E, Modesto C, Comas D, Puig A, Drechsel O, Ossowski S, Yagüe J, Merino R, Estivill X, Arostegui JI. Biallelic loss-of-function LACC1/FAMIN Mutations Presenting as Rheumatoid Factor-Negative Polyarticular Juvenile Idiopathic Arthritis. Sci Rep. 2019 Mar 14;9(1):4579Disclosure of Interests:None declared

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Impact of preservation of the azygos vein during surgical repair of esophageal atresia-tracheoesophageal fistula (EA-TEF): a systematic review and meta-analysis

Pediatric Surgery International ◽

10.1007/s00383-021-04913-2 ◽

2021 ◽

Author(s):

Deepika Kainth ◽

Sachit Anand ◽

Apoorv Singh ◽

Minu Bajpai

Keyword(s):

Systematic Review ◽

Esophageal Atresia ◽

Tracheoesophageal Fistula ◽

Surgical Repair ◽

Meta Analysis ◽

Azygos Vein

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Variable Expressivity of the Beckwith-Wiedemann Syndrome in Four Pedigrees Segregating Loss-of-Function Variants of CDKN1C

Genes ◽

10.3390/genes12050706 ◽

2021 ◽

Vol 12 (5) ◽

pp. 706

Author(s):

Angela Sparago ◽

Flavia Cerrato ◽

Laura Pignata ◽

Francisco Cammarata-Scalisi ◽

Livia Garavelli ◽

...

Keyword(s):

Cellular Proliferation ◽

Missense Variant ◽

Abdominal Wall Defects ◽

Loss Of Function ◽

Nonsense Mutations ◽

Molecular Defects ◽

Variable Expressivity ◽

Imprinting Disorder ◽

Perinatal Lethality ◽

Intrafamilial Variability

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by prenatal and/or postnatal overgrowth, organomegaly, abdominal wall defects and tumor predisposition. CDKN1C is a maternally expressed gene of the 11p15.5 chromosomal region and is regulated by the imprinting control region IC2. It negatively controls cellular proliferation, and its expression or activity are frequently reduced in BWS. In particular, loss of IC2 methylation is associated with CDKN1C silencing in the majority of sporadic BWS cases, and maternally inherited loss-of-function variants of CDKN1C are the most frequent molecular defects of familial BWS. We have identified, using Sanger sequencing, novel CDKN1C variants in three families with recurrent cases of BWS, and a previously reported variant in a woman with recurrent miscarriages with exomphalos. Clinical evaluation of the patients showed variable manifestation of the disease. The frameshift and nonsense variants were consistently associated with exomphalos, while the missense variant caused a less severe phenotype. Pregnancy loss and perinatal lethality were found in the families segregating nonsense mutations. Intrafamilial variability of the clinical BWS features was observed, even between siblings. Our data are indicative of severe BWS phenotypes that, with variable expressivity, may be associated with both frameshift and nonsense variants of CDKN1C.

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Rgs4 is a regulator of mTOR activity required for motoneuron axon outgrowth and neuronal development in zebrafish

Scientific Reports ◽

10.1038/s41598-021-92758-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Aya Mikdache ◽

Marie-José Boueid ◽

Lorijn van der Spek ◽

Emilie Lesport ◽

Brigitte Delespierre ◽

...

Keyword(s):

Nervous System ◽

G Protein ◽

Neural Development ◽

Neuronal Development ◽

Axon Outgrowth ◽

Rgs Proteins ◽

Protein Signaling ◽

Loss Of Function ◽

G Protein Coupled

AbstractThe Regulator of G protein signaling 4 (Rgs4) is a member of the RGS proteins superfamily that modulates the activity of G-protein coupled receptors. It is mainly expressed in the nervous system and is linked to several neuronal signaling pathways; however, its role in neural development in vivo remains inconclusive. Here, we generated and characterized a rgs4 loss of function model (MZrgs4) in zebrafish. MZrgs4 embryos showed motility defects and presented reduced head and eye sizes, reflecting defective motoneurons axon outgrowth and a significant decrease in the number of neurons in the central and peripheral nervous system. Forcing the expression of Rgs4 specifically within motoneurons rescued their early defective outgrowth in MZrgs4 embryos, indicating an autonomous role for Rgs4 in motoneurons. We also analyzed the role of Akt, Erk and mechanistic target of rapamycin (mTOR) signaling cascades and showed a requirement for these pathways in motoneurons axon outgrowth and neuronal development. Drawing on pharmacological and rescue experiments in MZrgs4, we provide evidence that Rgs4 facilitates signaling mediated by Akt, Erk and mTOR in order to drive axon outgrowth in motoneurons and regulate neuronal numbers.

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