Oral-Facial-Digital Syndrome Type 1: Further Clinical and Molecular Delineation in 2 New Families

2020 ◽  
Vol 57 (5) ◽  
pp. 606-615
Author(s):  
Sara Faily ◽  
Rahat Perveen ◽  
Kate Chandler ◽  
Jill Clayton-Smith
Keyword(s):  
Genetic Variants ◽  
Clinical Phenotype ◽  
Genetic Disorder ◽  
Molecular Diagnostic ◽  
Comparative Genomic ◽  
Syndrome Type ◽  
Loss Of Function ◽  
Renal Anomalies ◽  
Whole Exome

Objective: Oral-facial-digital syndrome type 1 (OFD1) [OMIM 311200] is a rare genetic disorder associated with congenital anomalies of the oral cavity, face, and digits. This condition is associated with mutations in the OFD1 gene. Our objective was to recruit patients with the OFD1 clinical phenotype without genetic confirmation, aiming to identify genetic variants in the OFD1 gene. Design: Three patients from 2 unrelated families were recruited into our study. We employed a variety of genomic techniques on these patients, including candidate gene analysis, array comparative genomic hybridization, whole-exome sequencing, and whole-genome sequencing. Results: We investigated 3 affected patients from 2 unrelated families with a clinical diagnosis of OFD1. We discovered a novel pathogenic dominant missense mutation c.635G>C (p.Arg212Pro) in the OFD1 gene in one family. A novel frameshift, loss-of-function mutation c.306delA (p.Glu103LysfsTer42) was detected in the affected patient in the second family. Conclusions: These new genetic variants will add to the spectrum of known OFD1 mutations associated with the OFD1 disorder. Our study also confirms the variable phenotypic presentation of OFD1 and its well-recognized association with central nervous system malformations and renal anomalies. Molecular diagnostic confirmation achieved in these families will have positive implications for their medical management.

scholarly journals Genotype-Phenotype Associations in Patients With Type-1, Type-2, and Atypical NF1 Microdeletions

2021 ◽  
Vol 12 ◽  
Author(s):  
Gergely Büki ◽  
Anna Zsigmond ◽  
Márta Czakó ◽  
Renáta Szalai ◽  
Gréta Antal ◽  
...  
Keyword(s):  
Clinical Phenotype ◽  
Somatic Mosaicism ◽  
Clinical Manifestations ◽  
Comparative Genomic ◽  
Loss Of Function ◽  
Large Tumor ◽  
Large Deletions ◽  
Hands And Feet

Neurofibromatosis type 1 is a tumor predisposition syndrome inherited in autosomal dominant manner. Besides the intragenic loss-of-function mutations in NF1 gene, large deletions encompassing the NF1 gene and its flanking regions are responsible for the development of the variable clinical phenotype. These large deletions titled as NF1 microdeletions lead to a more severe clinical phenotype than those observed in patients with intragenic NF1 mutations. Around 5-10% of the cases harbor large deletion and four major types of NF1 microdeletions (type 1, 2, 3 and atypical) have been identified so far. They are distinguishable in term of their size and the location of the breakpoints, by the frequency of somatic mosaicism with normal cells not harboring the deletion and by the number of the affected genes within the deleted region. In our study genotype-phenotype analyses have been performed in 17 mostly pediatric patients with NF1 microdeletion syndrome identified by multiplex ligation-dependent probe amplification after systematic sequencing of the NF1 gene. Confirmation and classification of the NF1 large deletions were performed using array comparative genomic hybridization, where it was feasible. In our patient cohort 70% of the patients possess type-1 deletion, one patient harbors type-2 deletion and 23% of our cases have atypical NF1 deletion. All the atypical deletions identified in this study proved to be novel. One patient with atypical deletion displayed mosaicism. In our study NF1 microdeletion patients presented dysmorphic facial features, macrocephaly, large hands and feet, delayed cognitive development and/or learning difficulties, speech difficulties, overgrowth more often than patients with intragenic NF1 mutations. Moreover, neurobehavior problems, macrocephaly and overgrowth were less frequent in atypical cases compared to type-1 deletion. Proper diagnosis is challenging in certain patients since several clinical manifestations show age-dependency. Large tumor load exhibited more frequently in this type of disorder, therefore better understanding of genotype-phenotype correlations and progress of the disease is essential for individuals suffering from neurofibromatosis to improve the quality of their life. Our study presented additional clinical data related to NF1 microdeletion patients especially for pediatric cases and it contributes to the better understanding of this type of disorder.

scholarly journals Novel Biallelic Loss-of-Function Variants in CEP290 Cause Joubert Syndrome in Two Siblings

2020 ◽  
Author(s):  
Xiang Wang ◽  
Zhu Zhang ◽  
Xueguang Zhang ◽  
Ying Shen ◽  
Hongqian Liu
Keyword(s):  
Intellectual Development ◽  
Genetic Disorder ◽  
Genetic Diagnosis ◽  
Joubert Syndrome ◽  
Comparative Genomic ◽  
Loss Of Function ◽  
Whole Exome ◽  
Number Variation ◽  
Exon 1

Abstract BackgroundJoubert Syndrome (JS) is a rare genetic disorder, which can be defined by brainstem malformation, cerebellar vermis hypoplasia and consequent “molar tooth sign” (MTS). JS always shares variety of phenotypes in development defects. With the development of next-generation sequencing, dozens of causative genes have been identified to JS so far. Here we investigated a JS case in two male siblings aged 4 and 10 years old and uncovered a novel pathogenesis through combined methods.Results The siblings shared similar features of nystagmus, delayed intellectual development. typical MTS, and abnormal morphology in fourth ventricle. Whole exome sequencing (WES) and chromosome comparative genomic hybridization (CGH) were then performed on the proband. Strikingly, a maternal inherited nonsense mutation (NM_025114.3: c.5953G>T [p.E1985*]) in CEP290 gene and a paternal inherited deletion in 12q21.32 including exon 1 to 10 of CEP290 gene were identified in the two affected siblings. We further confirmed the two variants by in vitro experiments: qPCR, and PCR-sequencing.Conclusions In this study, we first reported a novel causative mechanism of Joubert Syndrome: a copy number variation (CNV) compounding with a point mutation in CEP290 gene, which can be helpful in the genetic diagnosis of this disease.

Functional Hyperactivity in Long QT Syndrome Type 1 Pluripotent Stem Cell-Derived Sympathetic Neurons

2021 ◽  
Author(s):  
Annika Winbo ◽  
Suganeya Ramanan ◽  
Emily Eugster ◽  
Annika Rydberg ◽  
Stefan Jovinge ◽  
...  
Keyword(s):  
Pluripotent Stem Cell ◽  
Sympathetic Neurons ◽  
Compound Heterozygous ◽  
Syndrome Type ◽  
Loss Of Function ◽  
Long Qt ◽  
Action Potential Frequency ◽  
Qt Syndrome ◽  
Potential Frequency

Sympathetic activation is an established trigger of life-threatening cardiac events in long QT syndrome type 1 (LQT1). KCNQ1 loss-of-function variants, which underlie LQT1, have been associated with both cardiac arrhythmia and neuronal hyperactivity pathologies. However, the LQT1 sympathetic neuronal phenotype is unknown. Here we aimed to study human induced pluripotent stem cell (hiPSC)-derived sympathetic neurons (SNs) to evaluate neuronal functional phenotype in LQT1. We generated hiPSC-SNs from two LQT1 patients with a history of sympathetically triggered arrhythmia and KCNQ1 loss-of-function genotypes (c.781_782delinsTC and p.S349W/p.R518X). Characterisation of hiPSC-SNs was performed using immunohistochemistry, enzyme-linked immunosorbent assay and whole-cell patch clamp electrophysiology, and functional LQT1 hiPSC-SN phenotypes compared to healthy control (WT) hiPSC-SNs. hiPSC-SNs stained positive for tyrosine hydroxylase, peripherin, KCNQ1, and secreted noradrenaline. hiPSC-SNs at 60±2.2 days in vitro had healthy resting membrane potentials (-60±1.3 mV), and fired rapid action potentials with mature kinetics in response to stimulation. Significant hyperactivity in LQT1 hiPSC-SNs was evident via increased noradrenaline release, increased spontaneous action potential frequency, increased total inward current density, and reduced afterhyperpolarisation, compared to age-matched WT hiPSC-SNs. A significantly higher action potential frequency upon current injection and larger synaptic current amplitudes in compound heterozygous p.S349W/p.R518X hiPSC-SNs compared to heterozygous c.781_782delinsTC hiPSC-SNs was also observed, suggesting a potential genotype-phenotype correlation. Together our data reveal increased neurotransmission and excitability in heterozygous and compound heterozygous patient-derived LQT1 sympathetic neurons, suggesting that the cellular arrhythmogenic potential in LQT1 is not restricted to cardiomyocytes.

scholarly journals Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome

2016 ◽  
Vol 213 (7) ◽  
pp. 1163-1174 ◽  
Author(s):  
Marije E.C. Meuwissen ◽  
Rachel Schot ◽  
Sofija Buta ◽  
Grétel Oudesluijs ◽  
Sigrid Tinschert ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Genetic Disorders ◽  
Genetic Disorder ◽  
Congenital Infection ◽  
Infectious Agent ◽  
Negative Regulator ◽  
Type I ◽  
Loss Of Function

Pseudo-TORCH syndrome (PTS) is characterized by microcephaly, enlarged ventricles, cerebral calcification, and, occasionally, by systemic features at birth resembling the sequelae of congenital infection but in the absence of an infectious agent. Genetic defects resulting in activation of type 1 interferon (IFN) responses have been documented to cause Aicardi-Goutières syndrome, which is a cause of PTS. Ubiquitin-specific peptidase 18 (USP18) is a key negative regulator of type I IFN signaling. In this study, we identified loss-of-function recessive mutations of USP18 in five PTS patients from two unrelated families. Ex vivo brain autopsy material demonstrated innate immune inflammation with calcification and polymicrogyria. In vitro, patient fibroblasts displayed severely enhanced IFN-induced inflammation, which was completely rescued by lentiviral transduction of USP18. These findings add USP18 deficiency to the list of genetic disorders collectively termed type I interferonopathies. Moreover, USP18 deficiency represents the first genetic disorder of PTS caused by dysregulation of the response to type I IFNs. Therapeutically, this places USP18 as a promising target not only for genetic but also acquired IFN-mediated CNS disorders.

scholarly journals Intestinal pseudo-obstruction in a patient with Kleefstra syndrome

2021 ◽  
Vol 57 (4) ◽  
pp. 426-429
Author(s):  
Nikolina Golem ◽  
Harry Nikolić ◽  
Suzana Sršen Medančić ◽  
Ana Bosak Veršić
Keyword(s):  
Intestinal Motility ◽  
Genetic Disorder ◽  
Exploratory Laparotomy ◽  
Clinical Feature ◽  
Syndrome Type ◽  
First Case ◽  
Kleefstra Syndrome ◽  
Intestinal Pseudo Obstruction ◽  
Fluid Levels

Aim: To present a case of intestinal pseudo-obstruction in a paediatric patient with Kleefstra syndrome type 1 as a new clinical feature of this rare genetic disorder. Case report: A seven-year-old patient was admitted to the emergency department for nausea and vomiting. Clinical examination showed distended, meteoristic abdomen without detectable peristaltic sound. Abdominal X-ray revealed air-fluid levels and possible right subdiaphragmatic air collection. An urgent exploratory laparotomy was indicated. Intraoperatively, extremely dilated loops of small and large intestine up to the distal sigmoid colon were noted. No anatomical or mechanical causes of obstruction were found. The postoperative course was complicated by dysfunctional intestinal motility and urinary catheter-related infection which required prokinetics and intravenous antibiotic therapy. The patient was transferred to a paediatric centre specialized in intestinal motility disorders for further treatment. Conclusion: This is the first case of intestinal pseudo-obstruction described as a part of clinical presentation of Kleefstra syndrome type 1. Further research and re-evaluation of patients with KS1 is needed to determine if intestinal pseudo-obstruction is a new clinical manifestation depending on the size of the deletion or a repercussion of hypotonia sequential to an underlying syndrome.

scholarly journals Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1

2021 ◽  
Vol 218 (7) ◽  
Author(s):  
Paul Bastard ◽  
Elizaveta Orlova ◽  
Leila Sozaeva ◽  
Romain Lévy ◽  
Alyssa James ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Type I Interferons ◽  
Type I ◽  
Syndrome Type ◽  
Loss Of Function ◽  
Type I Ifns ◽  
Autoimmune Polyendocrine Syndrome ◽  
Life Threatening ◽  
Very High

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti–IFN-β and another anti–IFN-ε, but none had anti–IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.

scholarly journals Neurofibromin regulates metabolic rate via neuronal mechanisms in Drosophila

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Valentina Botero ◽  
Bethany A. Stanhope ◽  
Elizabeth B. Brown ◽  
Eliza C. Grenci ◽  
Tamara Boto ◽  
...  
Keyword(s):  
Metabolic Rate ◽  
Neurofibromatosis Type 1 ◽  
Genetic Disorder ◽  
Neurofibromatosis Type ◽  
Pathophysiological Mechanism ◽  
Metabolic Homeostasis ◽  
Loss Of Function ◽  
Dynamic Activity ◽  
Neuronal Mechanisms

AbstractNeurofibromatosis type 1 is a chronic multisystemic genetic disorder that results from loss of function in the neurofibromin protein. Neurofibromin may regulate metabolism, though the underlying mechanisms remain largely unknown. Here we show that neurofibromin regulates metabolic homeostasis in Drosophila via a discrete neuronal circuit. Loss of neurofibromin increases metabolic rate via a Ras GAP-related domain-dependent mechanism, increases feeding homeostatically, and alters lipid stores and turnover kinetics. The increase in metabolic rate is independent of locomotor activity, and maps to a sparse subset of neurons. Stimulating these neurons increases metabolic rate, linking their dynamic activity state to metabolism over short time scales. Our results indicate that neurofibromin regulates metabolic rate via neuronal mechanisms, suggest that cellular and systemic metabolic alterations may represent a pathophysiological mechanism in neurofibromatosis type 1, and provide a platform for investigating the cellular role of neurofibromin in metabolic homeostasis.

scholarly journals Case Report: A Novel PAX3 Mutation Associated With Waardenburg Syndrome Type 1

2021 ◽  
Vol 12 ◽  
Author(s):  
Qiuming Hu ◽  
Huazhong Ma ◽  
Jiawei Shen ◽  
Zongming Zhuang ◽  
Jianqiang Li ◽  
...  
Keyword(s):  
Case Report ◽  
Genetic Test ◽  
Novel Mutation ◽  
Present Report ◽  
Hereditary Disease ◽  
Chinese Family ◽  
Syndrome Type ◽  
Waardenburg Syndrome ◽  
Whole Exome

Background: Waardenburg Syndrome Type 1 (WS1) is a rare hereditary disease, which is usually caused by the mutations of PAX3 (paired box 3). Here, we reported a pedigree with WS1, which was caused by a novel mutation in PAX3.Case Report: In this present report, a 10-year-old boy and his twin sister from a Han Chinese family presented with iris pigmentary abnormality, synophrys, and broad and high nasal root. Their father presented premature whitening of the hair, but no iris pigmentary abnormality. Their aunts presented the same clinical characteristics with the twins and premature graying of hair. However, none of the patients reported hearing loss. The clinical diagnosis of the four patients from this pedigree was WS1. The whole exome sequencing (WES) revealed a novel mutation (c.959-5T>G) in the PAX3 gene, which could be responsible for the observed pathogenic of WS1 in this pedigree. The genetic test confirmed the diagnosis of WS1 in the four patients from the studied pedigree.Conclusion: This present study demonstrated that genetic test based on WES, an effective alternative to regular clinical examinations, helps diagnose WS1. The newly identified PAX3 gene mutation can expand the understanding of WS1.

Late diagnosis of chronic hypocalcemia due to autoimmune hypoparathyroidism

2021 ◽  
Vol 14 (6) ◽  
pp. e243299
Author(s):  
Maxime Teisseyre ◽  
Olivier Moranne ◽  
Sophie Renaud
Keyword(s):  
Calcium Supplementation ◽  
Genetic Disorder ◽  
Syndrome Type ◽  
Calcium Sensing Receptor ◽  
Basal Ganglia Calcification ◽  
Muscle Cramps ◽  
Oral Supplementation ◽  
Calcium Sensing ◽  
Autoimmune Polyendocrine Syndrome

Hypoparathyroidism is most often the result of postsurgical damage to the parathyroid glands but may occasionally be autoimmune hypoparathyroidism. In the latter context, activating antibodies directed against the calcium‐sensing receptor (CaSR) have been described. We hereby present the case of a patient suffering from chronic recurrent muscle cramps and paresthesia, presenting for a seizure due to hypocalcaemia. After eliminating the possibility of a genetic disorder, we searched for autoimmune hypoparathyroidism as there was no obvious cause of hypoparathyroidism. The search for anti-CaSR antibodies was positive. There was no argument for autoimmune polyendocrine syndrome type 1 so we concluded that it was isolated autoimmune hypoparathyroidism caused by activating antibodies to the CaSR. The patient was treated with vitamin D and calcium supplementation. The search for complications of hypoparathyroidism and hypercalciuria revealed basal ganglia calcification. The patient’s hypocalcaemia is now being kept under control with oral supplementation.

scholarly journals Novel Pathogenic Variant in the Cys110 Residue: A Genotype–Phenotype Report of a Patient with Norrie Disease

2019 ◽  
Vol 09 (02) ◽  
pp. 142-144
Author(s):  
Jaspreet Garcha ◽  
Angita Jain ◽  
Herjot Atwal ◽  
Pavalan Sevlam ◽  
Paldeep S. Atwal
Keyword(s):  
Retinal Detachment ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Phenotype ◽  
Hot Spot ◽  
Genetic Disorder ◽  
Male Infant ◽  
Norrie Disease ◽  
Pathogenic Variants ◽  
Whole Exome

AbstractNorrie disease is an X-linked genetic disorder caused by pathogenic mutations in the NDP. Here, we describe the clinical phenotype and genotype in a 19-week-old male infant with bilateral retinal detachment. Whole exome sequencing using available commercial methods on the proband revealed a hemizygous substitution in exon 3 of NDP, which suggests the etiology behind retinal detachment. This report not only adds to the expanding mutational spectrum of NDP-related retinopathies but also highlights the recurrence of pathogenic variants in the Cys110 residue, adding additional evidence to this residue as a potential mutational hot spot.

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