New Cohort of Patients With CEDNIK Syndrome Expands the Phenotypic and Genotypic Spectra

ObjectiveTo report 6 new patients with cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK) syndrome.MethodsClinical exome or targeted sequencing were performed to elucidate the molecular genetic cause in patients with neurocognitive abnormalities and brain imaging findings.ResultsCEDNIK syndrome is a rare genetic condition caused by biallelic pathogenic loss-of-function variants in synaptosomal-associated protein 29 (SNAP29), which encodes a vesicular membrane fusion protein. Clinical manifestations include significant developmental delay/intellectual disability (DD/ID), brain abnormalities, failure to thrive, and skin abnormalities. To date, 19 patients from 10 unrelated families with CEDNIK syndrome have been reported. We report 5 additional patients with homozygous predicted loss-of-function variants in SNAP29 and one with compound heterozygous variants: a frameshift SNAP29 variant and a 370 kb deletion on 22q11.2. All patients exhibit DD/ID, ichthyosis and/or palmoplantar keratoderma, and hypotonia. Four of 6 subjects had hypomyelinated white matter on MRI, 2 of 6 had early puberty, and 4 of 6 had strabismus, which were previously rarely reported. Other phenotypes were variably present, including dysmorphic features, feeding difficulties, and recurrent respiratory infections. The cohort includes 2 siblings with a c.2T>C variant who have a relatively milder phenotype, a patient with the most C-terminal variant yet described (c.622G>T), and 3 patients with previously described variants (c.354dupG, c.487dupA).ConclusionsThis cohort of 6 additional patients expands the genotypic and phenotypic spectrum of CEDNIK syndrome, highlighting previously under-recognized features such as hypomyelination, seizures, and early puberty. Owing to reduced penetrance of the skin phenotype, cerebral dysgenesis, and neuropathy, we propose renaming this syndrome SNAP29-related disorder.

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Recurrent respiratory viral diseases and chronic sequelae due to dominant negative IFIH1

10.1101/2020.07.01.20105379 ◽

2020 ◽

Author(s):

Christin L Deal ◽

Timothy J Thauland ◽

Rebecca Signer ◽

Stanley F Nelson ◽

Hane Lee ◽

...

Keyword(s):

Viral Infections ◽

Respiratory Infections ◽

Clinical Manifestations ◽

Dominant Negative ◽

Dominant Negative Effect ◽

Compound Heterozygous ◽

Loss Of Function ◽

Negative Effect ◽

Respiratory Viral Infections ◽

Compound Heterozygous Variants

Viral respiratory infections are the most common childhood infection worldwide. However, even common pathogens can have significant consequences in the context of patients with primary immunodeficiency diseases. More than half or viral infections annually are due to rhinovirus/enterovirus strains. Most clinical manifestations of viral infection are mild. However 3% of cases result in hospitalization in patients who have no other known risk factors. These patients may have an inborn error of immunity, a genetic susceptibility to viral infections. Here we present the case of an adult male who suffered respiratory viral infections his whole life and developed chronic, inflammatory damage to sinuses and lungs as a consequence. Genomic sequencing identified compound heterozygous variants in the IFIH1 gene, encoding the protein Melanoma Differentiation Association Protein 5 (MDA5), a RIG-I-like cytoplasmic sensor of RNA intracellular infections. We show a dominant negative effect on these variants on the level of interferon-induced expression of MDA5 protein. This work supports that loss-of-function variants in IFIH1 affect the sensing of viral infections. Underlying genomic variants may dictate the point at which recurrent, respiratory viral infections leave commonplace experience and incur lasting damage.

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Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

European Journal of Human Genetics ◽

10.1038/s41431-020-00769-7 ◽

2021 ◽

Author(s):

Meena Balasubramanian ◽

Alexander J. M. Dingemans ◽

Shadi Albaba ◽

Ruth Richardson ◽

Thabo M. Yates ◽

...

Keyword(s):

Intellectual Disability ◽

Protein Function ◽

Autism Spectrum ◽

Loss Of Function ◽

Mild Intellectual Disability ◽

Related Disorder ◽

Feeding Difficulties ◽

Facial Phenotype ◽

Novel Variants ◽

Common Behaviour

AbstractWitteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10–12.

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A Novel Mutation of ATP7B Gene in a Case of Wilson Disease

Medicina ◽

10.3390/medicina57020123 ◽

2021 ◽

Vol 57 (2) ◽

pp. 123

Author(s):

Cigdem Yuce Kahraman ◽

Ali Islek ◽

Abdulgani Tatar ◽

Özlem Özdemir ◽

Adil Mardinglu ◽

...

Keyword(s):

Wilson Disease ◽

Novel Mutation ◽

Molecular Genetic ◽

Molecular Genetic Analysis ◽

Compound Heterozygous ◽

Atp7b Gene ◽

Loss Of Function ◽

Clinical Presentations ◽

The Family ◽

The Brain

Wilson disease (WD) (OMIM# 277900) is an autosomal recessive inherited disorder characterized by excess copper (Cu) storage in different human tissues, such as the brain, liver, and the corneas of the eyes. It is a rare disorder that occurs in approximately 1 in 30,000 individuals. The clinical presentations of WD are highly varied, primarily consisting of hepatic and neurological conditions. WD is caused by homozygous or compound heterozygous mutations in the ATP7B gene. The diagnosis of the disease is complicated because of its heterogeneous phenotypes. The molecular genetic analysis encourages early diagnosis, treatment, and the opportunity to screen individuals at risk in the family. In this paper, we reported a case with a novel, hotspot-located mutation in WD. We have suggested that this mutation in the ATP7B gene might contribute to liver findings, progressing to liver failure with a loss of function effect. Besides this, if patients have liver symptoms in childhood and/or are children of consanguineous parents, WD should be considered during the evaluation of the patients.

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The Multifaceted Roles of MicroRNAs in Cystic Fibrosis

Diagnostics ◽

10.3390/diagnostics10121102 ◽

2020 ◽

Vol 10 (12) ◽

pp. 1102

Author(s):

Fatima Domenica Elisa De Palma ◽

Valeria Raia ◽

Guido Kroemer ◽

Maria Chiara Maiuri

Keyword(s):

Cystic Fibrosis ◽

Respiratory Infections ◽

Current Knowledge ◽

Pancreatic Insufficiency ◽

Clinical Manifestations ◽

Predictive Biomarkers ◽

Loss Of Function ◽

Gene Encoding ◽

Multisystemic Disease

Cystic fibrosis (CF) is a lifelong disorder affecting 1 in 3500 live births worldwide. It is a monogenetic autosomal recessive disease caused by loss-of-function mutations in the gene encoding the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR), the impairment of which leads to ionic disequilibria in exocrine organs. This translates into a chronic multisystemic disease characterized by airway obstruction, respiratory infections, and pancreatic insufficiency as well as hepatobiliary and gastrointestinal dysfunction. Molecular characterization of the mutational heterogeneity of CFTR (affected by more than 2000 variants) improved the understanding and management of CF. However, these CFTR variants are linked to different clinical manifestations and phenotypes, and they affect response to treatments. Expanding evidence suggests that multisystemic disease affects CF pathology via impairing either CFTR or proteins regulated by CFTR. Thus, altering the expression of miRNAs in vivo could constitute an appealing strategy for developing new CF therapies. In this review, we will first describe the pathophysiology and clinical management of CF. Then, we will summarize the current knowledge on altered miRNAs in CF patients, with a focus on the miRNAs involved in the deregulation of CFTR and in the modulation of inflammation. We will highlight recent findings on the potential utility of measuring circulating miRNAs in CF as diagnostic, prognostic, and predictive biomarkers. Finally, we will provide an overview on potential miRNA-based therapeutic approaches.

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Nagashima-Type Palmoplantar Keratosis: Clinical Characteristics, Genetic Characterization, and Clinical Management

BioMed Research International ◽

10.1155/2021/8841994 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Chao Huang ◽

Yali Yang ◽

Xingyu Huang ◽

Zongke Zhou

Keyword(s):

Clinical Management ◽

Clinical Characteristics ◽

Genetic Characterization ◽

Clinical Manifestations ◽

Compound Heterozygous ◽

Loss Of Function ◽

Gene Characterization ◽

Clade B ◽

Palmoplantar Keratosis ◽

Hands And Feet

Nagashima-type palmoplantar keratosis (NPPK) is the most prevalent palmoplantar keratoderma (PPK) in East Asia. Homozygous or compound heterozygous loss-of-function mutations in serpin peptidase inhibitor, clade B (ovalbumin), and member 70 (SERPINB7), which encodes members of the serine protease inhibitor superfamily, have been identified as the cause of NPPK. Clinical manifestations of NPPK include well-demarcated erythema, mild to moderate hyperkeratosis on the whole palm, and sole with transgrediens, extending to the dorsal surfaces of the hands and feet, inner wrists, ankles, and the Achilles tendon areas. In this study, we perform a review of relevant clinical cases aimed at elucidating the clinical characteristics, genetic characterization, differential diagnoses, and clinical management of NPPK. A better understanding of the clinical characteristics and pathogenic gene characterization of NPPK will enhance the diagnosis of NPPK, identify related diseases, and inform on the precise therapy and prognosis. Moreover, it will promote the awareness of NPPK in non-Asian regions.

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Mevalonate kinase deficiency syndrome: Single center experience

Rheumatology Science and Practice ◽

10.47360/1995-4484-2021-326-334 ◽

2021 ◽

Vol 59 (3) ◽

pp. 326-334

Author(s):

A. L. Kozlova ◽

V. O. Bludova ◽

V. I. Burlakov ◽

E. V. Raykina ◽

T. V. Varlamova ◽

...

Keyword(s):

Clinical Laboratory ◽

Molecular Genetic ◽

Clinical Manifestations ◽

Deficiency Syndrome ◽

Compound Heterozygous ◽

Mevalonate Kinase Deficiency ◽

Mevalonate Kinase ◽

Single Center Experience ◽

Full Remission ◽

Molecular Genetic Data

The aim of this study was to analyze the clinical, laboratory and molecular genetic data of 26 patients (15 boys, 11 girls) diagnosed with mevalonate kinase deficiency syndrome (MKD).Subjects and methods. The age of MKD manifestation ranged from 0 to 30.0 months (M – 1.5 months). Clinical manifestations and their severity were extremely diverse: from symptoms resembling Marshall’s syndrome to severe systemic manifestations with respiratory failure, hepatosplenomegaly and pancytopenia.Results/Conclusion. All patients had homozygous/compound-heterozygous mutations in the MVK gene, including 10 newly described variants. In all 20 patients, who have been treated with IL-1 inhibitors long enough to assess the effect of the treatment, drastic improvement of the condition was noted, but only in 17/20 patients achieved full remission.

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Pyruvate kinase deficiency: epidemiology, molecular analyses and modern diagnostic approaches (literature review)

Russian Journal of Pediatric Hematology and Oncology ◽

10.21682/2311-1267-2020-7-2-86-93 ◽

2020 ◽

Vol 7 (2) ◽

pp. 86-93

Author(s):

A. V. Bankole ◽

E. A. Chernyak

Keyword(s):

Pyruvate Kinase ◽

Hemolytic Anemia ◽

Molecular Genetic ◽

Clinical Manifestations ◽

Diagnostic Methods ◽

Compound Heterozygous ◽

Red Cell ◽

Molecular Genetic Study ◽

Pyruvate Kinase Deficiency ◽

Diagnostic Approaches

Red cell pyruvate kinase deficiency is the most common glycolytic defect causing congenital nonspherocytic hemolytic anemia. Pyruvate kinase is the enzyme involved in the last step of glycolysis – the transfer of a phosphate group from phosphoenolpyruvate producing the enolate of pyruvate and ATP (50 % of total energy ATP of erythrocytes). ATP deficiency directly shortened red cell lifespan. Affected red blood cells are destroyed in the splenic capillaries, leading to the development of chronic hemolytic anemia. It is an autosomal recessive disease, caused by homozygous and compound heterozygous mutations in the PKLR gene. There are no exact data on the incidence of pyruvate kinase deficiency, but the estimated frequency varies from 3: 1,000,000 to 1:20,000. The clinical features of the disease and the severity are highly variable. Diagnosis of pyruvate kinase deficiency is based on the determination of pyruvate kinase activity and molecular genetic study of the PKLR gene. The variety of clinical manifestations, possible complications, as well as the inaccessibility of diagnostic methods complicate the diagnosis.

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Biallelic ERBB3 loss-of-function variants are associated with a novel multisystem syndrome without congenital contracture

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-019-1241-z ◽

2019 ◽

Vol 14 (1) ◽

Author(s):

Niu Li ◽

Yufei Xu ◽

Yi Zhang ◽

Guoqiang Li ◽

Tingting Yu ◽

...

Keyword(s):

Postnatal Growth ◽

Compound Heterozygous ◽

Loss Of Function ◽

Atrioventricular Canal ◽

Multiple Systems ◽

Feeding Difficulties ◽

Functional Studies ◽

Pathogenic Variants ◽

Compound Heterozygous Variants

Abstract Background Gain-of-function pathogenic variants of the Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene contribute to the occurrence and development of a variety of human carcinomas through activation of phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) signaling. ERBB3 gene homozygous germline variants, whose loss of function may cause autosomal recessive congenital contractural syndrome, were recently identified. This study aims to identify the disease-causing gene in a Chinese pedigree with variable phenotypes involving multiple systems, including developmental delay, postnatal growth retardation, transient lower limb asymmetry, facial malformations, atrioventricular canal malformation, bilateral nystagmus and amblyopia, feeding difficulties, immunodeficiency, anemia, and liver damage, but without congenital contracture. Methods Trio-whole exome sequencing (WES) was performed to identify the disease-causing gene in a 24-month-old Chinese female patient. The pathogenicity of the identified variants was evaluated using in silico tools and in vitro functional studies. Results Trio-WES revealed compound heterozygous variants of c.1253 T > C (p.I418T) and c.3182dupA (p.N1061Kfs*16) in the ERBB3 gene. Functional studies showed that p.I418T resulted in normal expression of ERBB3, which was capable of interacting with ERBB2. However, the variant impaired ERBB3 phosphorylation, consequently blocking ERBB2 phosphorylation and AKT and ERK activation. The truncated protein resulting from the c.3182dupA variant also lacked the capacity to activate downstream signaling pathways. Conclusions We report the first patient with a novel multisystem syndrome disorder without congenital contracture resulting from biallelic loss-of-function variants of ERBB3.

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Características clínicas y epidemiológicas de pacientes pediátricos con fibrosis quística en Panamá, de Enero 2008 a Diciembre 2017

Revista Pediátrica de Panamá ◽

10.37980/im.journal.rspp.20191581 ◽

2020 ◽

pp. 4-12

Author(s):

Ana Karina Coronado ◽

Ricardo A Chanis ◽

Luis Coronado

Keyword(s):

Cystic Fibrosis ◽

Respiratory Infections ◽

Genetic Defect ◽

Clinical Manifestations ◽

Case Fatality ◽

Failure To Thrive ◽

City Hospital ◽

Age Of Diagnosis ◽

First Year Of Life ◽

Epidemiological Characteristics

Introducción.La presente investigación plantea como objetivo principal, describir las características clínicas y epidemiológicas de la fibrosis quística (FQ) en Panamá, que nos permiten hacer el diagnóstico temprano y dar a conocer las características bioquímicas, fenotípicas y morbilidades asociadas para así poder mejorar las necesidades de los pacientes con esta enfermedad. Materiales y métodos. Se realizó un estudio retrospectivo de los pacientes con diagnóstico de fibrosis quística entre el mes de enero 2008 a diciembre 2017, en los hospitales en Ciudad de Panamá: Hospital del Niño Dr. José Renán Esquivel, Hospital de Especialidades Pediátricas y en Chiriquí Hospital José Domingo de Obaldía previa aprobación de las autoridades correspondientes.Se analizaron las características demográficas, fenotípicas, resultados bioquímicos, complicaciones y tratamiento de pacientes con diagnóstico de Fibrosis quística. Mediante un diseño descriptivo, se analizó la información de las mismas.Resultados.El promedio de edad para el diagnóstico de fibrosis quística fue de 2.8 años. El 52% correspondía a sexo masculino y 48% a sexo femenino. El promedio de hospitalización previo al diagnóstico de Fibrosis quística fue de 3.8. En el 72 % de los pacientes los primeros síntomas aparecieron antes del primer año de vida.En la mayoría de los pacientes las manifestaciones clínicas fueron una combinación de síntomas gastrointestinales y/o nutricionales y respiratorios (96 y 92% respectivamente).En el 44% de los pacientes se realizó examen genético molecular. De acuerdo con la clasificación del defecto genético, el 20 % de los pacientes eran del grupo delta F 508. La edad promedio de sobrevida es 8.2, años. Durante el período 2008-2017 se registraron 6 defunciones de pacientes con fibrosis quística, lo que corresponde a una tasa de letalidad del 22%.Conclusiones.Los resultados de nuestro estudio mostraron condiciones tales como falla de medro, infecciones respiratorias recurrentes, esteatorrea como la forma de presentación clínica más frecuente. Encontramos correlación con la literatura con la presencia de manifestaciones respiratorias asociadas a compromiso nutricional. El genotipo no se hace a todos los pacientes, reconociendo la importancia de esta valoración por la disponibilidad y costos de las pruebas genéticas. A pesar del diagnóstico temprano, nuestros pacientes cursan con compromiso nutricional importante. En los últimos años se ha evidenciado una media de edad de diagnóstico más temprana comparada con años anteriores. Es necesaria la estandarización de pruebas diagnósticas y de seguimiento, puesto que no todos los pacientes cumplen en su totalidad con los criterios diagnósticos. En la actualidad, un alto índice de sospecha clínica es obligatorio para su detección e intervención inmediata del tratamiento hasta actualización de las instalaciones de diagnóstico. Abstract Introduction .The main objective of the present investigation is to describe the clinical and epidemiological characteristics of cystic fibrosis (CF) in Panama, which allow us to make a nearly diagnosis and make known the biochemical, phenotypic and associated morbidities in order to improve the needs of the patients with this disease. Materials and methodsA retrospective study of patients diagnosed with cystic fibrosis was conducted between January 2008 and December 2017, in hospitals in Panama City: Hospital del Niño Dr. José Renán Esquivel, Hospital de Especialidades Pediátricas Omar Torrijos Herrera and Hospital José Domingo de Obaldía, upon approval of the corresponding authorities. We analyzed the demographic, phenotypic characteristics, biochemical results, complications and treatment of patients diagnosed with Cystic Fibrosis. Through a descriptive design, the information of them was analyzed. Results. The average age for the diagnosis of cystic fibrosis was of 2.8 years, 52% corresponded tomale and 48% female. The average number of hospitalizations prior tothe diagnosis of cystic fibrosis was 3.8. In 72% of the patients the first symptoms appeared before the first year of life. In the majority of patients, the clinical manifestations were a combination of gastrointestinal and / or nutritional and respiratory symptoms (96 and 92% respectively). Molecular genetics examination was performed in 44% of the patients. According to the classification of the genetic defect, 20% of the patients were from the delta F 508 group. The average age of survival is 8.2 years. During the period 2008-2017 there were 6 deaths of patients with cystic fibrosis, which corresponds to a case-fatality rate of 22%.Conclusions.The results of our study showed conditions such as failure to thrive, recurrent respiratory infections, steatorrhea as the most frequent form of clinical presentation. We found correlation with the literature with the presence of respiratory manifestation associated with nutritional compromise. The genotype is not made to all patients, recognizing the importance of assessing the availability and costs of genetictesting. Despite early diagnosis, our patients have an important nutritional commitment. In recenty ears there is evidence of a lower age of diagnosis earlier compared with previous years.It is necessary to standardize diagnostic tests and follow-up, since not all patients fully meet the diagnostic criteria. At present, a high index of clinical suspicion is mandatory for early detection and immediate intervention of the treatment until updating of the diagnostic facilities.

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Autosomal Dominant ANO5-Related Disorder Associated With Myopathy and Gnathodiaphyseal Dysplasia

Neurology Genetics ◽

10.1212/nxg.0000000000000612 ◽

2021 ◽

Vol 7 (4) ◽

pp. e612

Author(s):

Aziz Shaibani ◽

Shaida Khan ◽

Marwan Shinawi

Keyword(s):

Bone Fractures ◽

Molecular Genetic ◽

In Silico Analysis ◽

Missense Variant ◽

Neuromuscular Disorder ◽

Muscle Disease ◽

Molecular Testing ◽

Loss Of Function ◽

Related Disorder ◽

Functional Studies

ObjectiveTo investigate the molecular basis of muscle disease and gnathodiaphyseal dysplasia (GDD) in a large kindred with 11 (6 women and 5 men) affected family members.MethodsWe performed clinical assessment of 3 patients and collected detailed clinical and family history data on 8 additional patients. We conducted molecular genetic analyses on 5 patients using comprehensive neuromuscular disorder panels, exome sequencing (ES), and targeted testing for specific genetic variants. We analyzed the segregation of the muscle and bone phenotypes with the underlying molecular cause.ResultsThe unique clinical presentation of recurrent episodes of rhabdomyolysis associated with muscle cramps, hyperCKemia, muscle hypertrophy, with absent or mild muscle weakness, as well as cemento-osseous lesions of the mandible, with or without bone fractures and other skeletal abnormalities, prompted us to look for the underlying molecular cause of the disorder in this kindred. Molecular testing revealed a missense variant in anoctamin 5 (ANO5) designated as c.1538C>T; p.Thr513Ile, which was previously described in a large kindred with GDD. In silico analysis, searching publicly available databases, segregation analysis, as well as functional studies performed by another group provide strong evidence for pathogenicity of the variant. ES data in the proband excluded the contribution of additional genetic factors.ConclusionsThis report described the coexistence of muscle and bone phenotypes in the same patients with ANO5-related disorder. Our data challenge recent results that suggested complete dichotomy of these phenotypes and the proposed loss-of-function and gain-of-function mechanisms for the skeletal and muscle phenotypes, respectively.

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