Whole-exome sequencing identified a homozygous novel RAG1 mutation in a child with omenn syndrome

Introduction and objectives Omenn syndrome (OS) is a very rare type of severe combined immunodeficiencies manifested with erythroderma, eosinophilia, hepatosplenomegaly, lymph-adenopathy, and elevated level of serum IgE. OS is inherited with an autosomal recessive mode of inheritance. Germline mutations in the human RAG1 gene cause OS. Materials and methods In this study, we investigated a 2-month-old boy with cough, mild anaemia, pneumonia, immunodeficiency, repeated infection, feeding difficulties, hepatomegaly, growth retardation, and heart failure. Parents of the proband were phenotypically normal. Results Karyotype analysis and chromosomal microarray analysis found no chromosomal structural abnormalities (46, XY) and no pathogenic copy number variations (CNVs) in the proband. Whole-exome sequencing identified a novel homozygous single nucleotide deletion (c.2662delC) in exon 2 of the RAG1 gene in the proband. Sanger sequencing confirmed that both the proband parents were carrying this variant in a heterozygous state. This variant was not identified in two elder sisters and one elder brother of the proband and in the 100 ethnically matched normal healthy individuals. This novel homozygous deletion (c.2662delC) leads to the frameshift, which finally results in the formation of the truncated protein (p.Leu888Phefs*3) V(D)J recombination-activating protein 1 with 890 amino acids compared with the wildtype V(D)J recombination-activating protein 1 of 1043 amino acids. Hence, it is a loss-of-function variant. Conclusion Our present study expands the mutational spectrum of the RAG1 gene associated with OS. We also strongly suggested the importance of whole-exome sequencing for the genetic screening of patients with OS (AU)

Los linajes Victoria y Yamagata de los virus gripales B, desconocidos y poco valorados / The Victoria and Yamagata Lineages of Influenza B Viruses, unknown and undervalued

El virus gripal B pertenece a la familia Orthomyxoviriridae y al género Influenzavirus B. Presenta un genoma de tipoARN negativo formado por unos 14.648 nucleótidos divididosen ocho segmentos distintos que codifican unas 11 proteínas.Antes de 1980 todos los virus de la gripe B pertenecían a unúnico linaje genético; pero en este año emergieron dos linajesantigénica y genéticamente distintos que se denominaron B/Victoria/2/1987 y B/Yamagata/16/1988. Se han podido demostrar procesos de intercambio genético intralinajes y entrelinajes; de ellos los mas frecuentes son aquellos en los que el linajeVictoria adquiere genes del linaje Yamagata. Se ha propuestoque las diferencias en las dinámicas evolutivas de los dos linajesse deban a las diferentes preferencias de unión de la hemaglutinina gripal al receptor celular. El linaje Victoria ha mostradocapacidad para unirse a los receptores celulares con restos deácido siálico en las posiciones a-2,3 y a-2,6; mientras que ellinaje Yamagata lo hace exclusivamente en las posiciones humanas a-2,6 del tracto respiratorio. La escasa circulación enlos últimos meses podría haber contribuido a la eliminación(“extinción”) temporal del linaje Yamagata. Desde 2017 la casitotalidad de las cepas de este linaje pertenecen al clado 3A,cuando con anterioridad se detectaban clados múltiples circulando. Aunque este clado 3A es diverso a nivel genético y haadquirido mutaciones sustitutivas en el gen de la hemaglutinina, éstas no han determinado cambios antigénicos significativos que hayan obligado a sustituir su componente antigénico(B/Pukhet/3073/2013) en la vacuna gripal desde 2015. (AU)

The influenza virus B belongs to the family Orthomyxoviriridae and to the genus Influenzavirus B. It has a negativeRNA-type genome made up of about 14,648 nucleotides divided into eight different segments that encode about 11 proteins.Before 1980 all influenza B viruses belonged to a single geneticlineage; but in this year two antigenically and genetically distinct lineages emerged which were named B/Victoria/2/1987and B/Yamagata/16/1988. Intralineage and interlineage genetic exchange processes have been demonstrated; The most frequent of them are those in which the Victoria lineage acquiresgenes from the Yamagata lineage. It has been proposed thatthe differences in the evolutionary dynamics of the two lineages are due to the different binding preferences of influenzahemagglutinin to the cellular receptor. The Victoria lineage hasshown the ability to bind to cell receptors with sialic acid residues at the α-2,3 and α-2,6 positions; whereas the Yamagatalineage does so exclusively in the human α-2,6 positions of therespiratory tract. Low circulation in recent months may havecontributed to the temporary elimination (“extinction”) of theYamagata lineage. Since 2017, almost all of the strains of thislineage belong to clade 3A, when previously multiple circulating clades were detected. Although this clade 3A is diverse atthe genetic level and has acquired surrogate mutations in thehemagglutinin gene, these have not determined significantantigenic changes that have made it necessary to replace itsantigenic component (B/Pukhet/3073/2013) in the influenzavaccine since 2015. (AU)

Genograma y árbol genealógico / Genogram and genealogical tree

El genograma y el árbol genealógico son herramientas de representación gráfica de la familia que, aunque comparten similitudes, tienen una funcionalidad y significados diferentes. Si bien el objetivo básico del primero es representar la estructura familiar y las relaciones entre sus miembros, el segundo pretende la identificación del patrón de herencia y de rasgos heredables, aunque su uso y aplicaciones van mucho más allá. Por otra parte, la representación gráfica en ambas herramientas se encuentra normalizada con símbolos similares, aunque algunos de ellos con significado distinto. Tanto una como otra, son utilizadas por el médico de familia, y éste debe tener las competencias necesarias para su manejo efectivo. En este trabajo se pretende mejorar dichas competencias al definir las principales diferencias de una y otra herramienta, establecer los elementos básicos para la construcción e interpretación del árbol genealógico, además de señalar su utilidad clínica y sus usos más frecuentes (AU)

A genogram and a genealogical tree are graphic representations of families that share similarities but have different functionality and meanings. While the first basic objective is to represent the family structure and the relationships between its members, the second seeks to identify the inheritance pattern and inheritable traits, although its use and applications go much further. Graphic representation is normalized with similar symbols, although some of them have different meanings. Both are used by family doctors, and they must have the necessary skills for their effective management. This work aims to improve these skills by defining the main differences between the two tools, establishing the basic elements for the construction and interpretation of a genealogical tree, and pointing out its clinical utility and its most frequent uses (AU)

A novel homozygous RAG1 mutation is associated with severe combined immunodeficiency and neurological presentations

Introduction and objectives: Severe combined immunodeficiency (SCID) is a subset of primary immunodeficiency diseases caused by a hereditary deficiency of the adaptive immune system. Mutation in recombination activating gene (RAG) is known as the underlying genetic cause of SCID. RAG protein plays a pivotal role in V(D)J recombination which is the main process to assemble lymphocyte antigen receptors during T- and B-cell development. The patients are characterized by recurrent infections, failure to thrive, chronic diarrhea, and fever, in early infancy. Herein, we present a case of SCID with rare neurological manifestations affected by a mutation in RAG1. Patients and methods: The patient was a 15-month-old infant born to a consanguineous family. She was presented with neurological abnormalities including facial nerve palsy, seizure, and decreased consciousness. Next-generation sequencing (NGS)-based primary immunodeficiency disease (PID)-gene panel screen and Sanger sequencing were performed to identify the genetic mutation. Results: We found a novel homozygous missense mutation in RAG1, c.1210C>T,p.Arg404Trp, which was predicted to be deleterious (combined annotation dependent depletion, CADD score of 27.4). Both parents were heterozygous carriers for this mutation. According to her laboratory data, both T cell and B cell numbers were decreased and the patient was diagnosed as RAG1- SCID. Conclusions: SCID is a pediatric emergency with a variety of manifestations in infants. Therefore, accurate diagnosis importantly in the case of rare manifestations must be considered in these patients. Our findings point toward the importance of genetic assessment for early diagnosis and timely treatment of this disorder (AU)

Novel BTK mutation in X-linked agammaglobulinemia: Report of a 17-year-old male

Introduction and objectives: X-linked agammaglobulinemia (XLA), the first known primary immunodeficiency, is caused by rare mutations in Bruton’s tyrosine kinase (BTK) gene. Mutations in the BTK gene lead to a failure in the development and maturation of B-cell linage. A decreased number of B-cells results in agammaglobulinemia and increased susceptibility to a variety of infections. Therefore, patients with XLA usually manifest with repetitive bacterial infections, such as upper respiratory tract infections, septic arthritis, osteomyelitis, and urinary tract infections, since their infancy. Patients We report a 17-year-old Iranian boy with XLA, referred to us with a history of severe and recurrent episodes of bacterial infections for a period of six years. Results Genetic analysis using the whole Exome sequencing revealed a hemizygous missense mutation in the BTK gene (c.428 A > T, p.His143Leu). Conclusion To our knowledge, c.428 A > T has not been reported in the BTK gene (AU)

Ataxia por déficit de vitamina E en una familia con posible afectación cardíaca / Vitamin E deficiency ataxia in a family with possible cardiac involvement

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Familia española portadora de una mutación en heterocigosis compuesta en el gen SPG7: de la incertidumbre a la realidad clínica / A Spanish family with a compound heterozygous mutation in SPG7: From uncertainty to clinical reality

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Diagnóstico de un caso de ceguera nocturna estacionaria congénita tipo 2 ligada al cromosoma X mediante electrorretinografía y secuenciación del gen CACNA1F / Diagnosis of an X-linked type 2 congenital stationary night blindness using electroretinography and CACNA1F sequencing

Un varón de 4 años, sin antecedentes relevantes, consulta por disminución de agudeza visual bilateral, más acusada en condiciones escotópicas, que no mejora con corrección óptica. No se aprecian alteraciones fundoscópicas significativas, por lo que se sospecha una distrofia retiniana. La secuenciación del gen CACNA1F detecta la mutación c.3081C > A (p.Tyr1027Ter), que se ha producido de novo en la madre del paciente. Esta mutación, en el contexto clínico referido y con un patrón electronegativo compatible, establece el diagnóstico de ceguera nocturna estacionaria congénita tipo 2 ligada al cromosoma X. La electrofisiología y el estudio genético deben formar parte del protocolo diagnóstico de cualquier pérdida de visión inexplicada en niños. La descripción, la nomenclatura y la clasificación de las distrofias retinianas hereditarias con base en sus características genotípicas y electrorretinográficas evita los errores diagnósticos derivados de su habitual superposición clínica y fenotípica

A 4-year-old boy, with no history of relevance, presented with bilateral visual impairment, more so in scotopic conditions, and did not improve with optical correction. No significant funduscopic abnormalities were seen, leading to a suspicion of retinal dystrophy. Sequencing of the CACNA1F gene detected the c.3081C > A (p.Tyr1027Ter) mutation, which had occurred de novo in the patient's mother. This mutation, in the aforementioned clinical context, and with a compatible electronegative pattern, establishes the diagnosis of X-linked type 2 congenital stationary night blindness. Electrophysiology and genetic testing should be part of the diagnostic protocol for any unexplained loss of vision in children. The description, nomenclature and classification of hereditary retinal dystrophies based on their genotypic and electroretinograpic characteristics, avoids diagnostic errors due to their usual clinical and phenotypic overlap

SPTB related spherocytosis in a three-generation family presenting with kidney failure in adulthood due to co-occurrence of UMOD disease causing variant / Esferocitosis relacionada con SPTB en tres generaciones de una familia con insuficiencia cardíaca en la edad adulta debido a la presentación conjunta de la variante de UMOD causante de la enfermedad

BACKGROUND: Hereditary spherocytosis is clinically and genetically heterogeneous disorder and its clinical characteristics are spherocytosis, anaemia, jaundice and splenomegaly. The aetiology is associated to the genes encoding proteins involved in the interaction between the erythrocyte membrane and the lipid bilayer. Causative variants in BetaI-spectrin (SPTB) gene presenting as mild to moderately severe disease are responsible for approximately 25% cases in the USA and Europe. Among kidney disease, isolated cases of nephrotic syndrome due to membranoproliferative glomerulonephritis and macroscopic haematuria with proteinuria due to IgA nephropathy were previously reported in patients with SPTB deficiency. OBJECTIVE: Seven patients from the same family with spherocytosis were evaluated to assess the kidney failure presented in all affected adult patients. METHODS: Clinical, radiological and laboratory investigations were issued to evaluate the spherocytosis and kidney disease. In selected patients, we also performed genetics testing with next generation sequencing of genes related to hereditary spherocytosis, inherited glomerular disorders and tubulo-interstitial kidney disease. RESULTS: Among the family members with spherocytosis, two adults had end-stage kidney disease and one chronic kidney disease stage 4 with unspecific histopathological findings of interstitial fibrosis/tubular atrophy and glomerulosclerosis. At the time, there were no signs of kidney disease present in four paediatric patients. Novel nonsense variant in SPTB gene (NM_001024858; c.4796G>A; p.Trp1599Ter) was detected in all family members with spherocytosis and was predicted to be disease causing. Furthermore, all adult patients with kidney failure and two paediatric cousins of the index patients were heterozygous for the UMOD gene variant (NM_003361.3:c.552G > C, NP_003352.2:p.Trp184Cys) previously reported in patients with tubulo-interstitial kidney disease. UMOD variant was not present in the index patients. CONCLUSIONS: The co-occurrence of any two rare inherited disorders is extremely rare, while to our knowledge the co-occurrence of genetically confirmed HS and autosomal dominant tubulo-interstitial kidney disease (ADTKD) has previously not been reported. It is not possibly to evaluate whether the haemolytic crises due to HS are influencing the progression of the UMOD related renal disease, since the UMOD related ADTKD characteristics in general and in here presented family are extremely variable. Nevertheless, the observed kidney disease in the family is warranting the regular nephrological examinations in UMOD positive paediatric patients in the family in order to recognise hyperuricemia and treat it as early as possible. This is emphasising the importance of serum uric acid detection in routine laboratory screening of paediatric patients in order to identify early signs of tubular injury indicating possible ADTKD

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Chronic pancreatitis with polycystic kidney disease: A rare coincidence? / Pancreatitis crónica con enfermedad renal poliquística: ¿una rara coincidencia?

INTRODUCTION: In children, chronic pancreatitis (CP) is usually associated with anatomical anomalies of the pancreas and biliary tract or is genetically determined. Autosomal dominant polycystic kidney disease (ADPKD) may present with extrarenal cyst formation, sometimes involving the pancreas. Large enough, these cysts may cause pancreatitis in ADPKD patients. Case presentation: Herein, we present a case of a 12-year-old Caucasian girl with recurrent pancreatitis with no identifiable traumatic, metabolic, infectious, drug, or immunologic causes. Structural anomalies of the pancreas, including cysts, were ruled out by imaging. However, bilateral cystic kidneys were found as an incidental finding. Her family history was negative for pancreatitis, but positive for polycystic kidney disease. Molecular analysis of ADPKD-causing mutations revealed a novel c.9659C>A (p.Ser3220*) mutation in the PKD1 gene confirming the clinical suspicion of ADPKD. Although CP may rarely occur as an extrarenal manifestation of ADPKD with pancreatic cysts, it is unusual in their absence. Thus, molecular analysis of pancreatitis susceptibility genes was performed and a homozygous pathologic c.180C>T (p.G60=) variant of the CTRC gene, known to increase the risk of CP, was confirmed. CONCLUSION: This is the first reported case of a pediatric patient with coincidence of genetically determined CP and ADPKD. Occurrence of pancreatitis in children with ADPKD without pancreatic cysts warrants further investigation of CP causing mutations

INTRODUCCIÓN: En niños, la pancreatitis crónica (CP, por sus siglas en inglés) generalmente se asocia con anomalías anatómicas del páncreas y el tracto biliar, o está genéticamente determinada. La enfermedad renal poliquística autosómica dominante (ADPKD, por sus siglas en inglés) puede presentarse con la formación de quistes extrarrenales, que a veces afecta al páncreas. Suficientemente grandes, estos quistes pueden causar pancreatitis en pacientes con ADPKD. Presentación del caso: Presentamos el caso de una niña caucásica de 12 años con pancreatitis recurrente sin causas identificables traumáticas, metabólicas, infecciosas, farmacológicas o inmunológicas. Las anomalías estructurales del páncreas, incluidos los quistes, se descartaron mediante imágenes. Sin embargo, los riñones quísticos bilaterales se encontraron como un hallazgo accidental. Su historia familiar fue negativa para la pancreatitis, pero positiva para la enfermedad renal poliquística. El análisis molecular de las mutaciones causantes de ADPKD reveló una nueva mutación c.9659C>A (p.Ser3220*) en el gen PKD1 que confirma la sospecha clínica de ADPKD. Aunque la CP rara vez ocurre como una manifestación extrarrenal de ADPKD con quistes pancreáticos es inusual. Por lo tanto, se realizó el análisis molecular de los genes de susceptibilidad a pancreatitis y se confirmó una variante homocigótica patológica c.180C>T (p.G60=) del gen CTRC, que se sabe que aumenta el riesgo de CP. CONCLUSIÓN: Este es el primer caso reportado de un paciente pediátrico con coincidencia de CP y ADPKD genéticamente determinados. La aparición de pancreatitis en niños con ADPKD sin quistes pancreáticos justifica una mayor investigación de CP que causan mutaciones

Nueva variante patogénica en el gen SPAST en una familia española afecta de paraplejía espástica hereditaria / A novel pathogenic variant of the SPAST gene in a Spanish family with hereditary spastic paraplegia

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Nueva mutación en el gen ACTA2 (pMet84Val) en una familia con aneurismas de aorta familiares no sindrómicos / New mutation in the ACTA2 gene (pMet84Val) in a family with nonsyndromic familial aortic aneurysms

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Hiperparatiroidismo familiar aislado asociado al gen HRPT2 / Familial isolated hyperparathyroidism due to HRPT2 mutation

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Síndrome del cromosoma X frágil / Fragile X syndrome

El síndrome del X frágil (SXF) es un trastorno hereditario ligado al cromosoma X que afecta sobre todo a hombres y ocasiona principalmente discapacidad intelectual. Además se asocia con el fenómeno de anticipación, aumentando la gravedad en generaciones sucesivas. La etiología es una mutación por expansión de tripletes de nucleótidos CGG en el gen FMR1 localizado en la región Xq27.3 del cromosoma X, con una prevalencia en hombres de 1/4.000 y en mujeres de 1/6.000. En las familias afectadas podemos encontrarnos con mujeres con menopausia precoz y personas con el síndrome FXTAS, que cursa con temblor/parkinsonismo (AU)

Fragile X syndrome (FXS) is an inherited disease linked to the X chromosome that mainly affects men and that causes principally intellectual disability. In addition it is associated with the phenomenon of genetic anticipation, increasing severity in successive generations. Its etiology is a mutation by expansion of CGG trinucleotide repeats in the FMR1 gene located at region Xq27.3 of the X chromosome with a prevalence in men of 1/4,000 and in women of 1/6,000. In affected families we can find women with premature menopause and persons with FXTAS syndrome, that causes tremor/parkinsonism (AU)

Utilidad de una consulta de enfermedades renales hereditarias: un enfoque diferente basado en el árbol genealógico / Utility of a consultation on hereditary kidney diseases: A different approach based on the family tree

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Paraplejía espástica hereditaria ligada al cromosoma X por mutación en el gen L1CAM: presentación de tres casos del síndrome CRASH / X-linked hereditary spastic paraplegia due to mutation in the L1CAM gene: three cases reports of CRASH syndrome

Introducción. La paraplejía espástica hereditaria (PEH) representa un conjunto de cuadros clínicos neurodegenerativos que se caracteriza por pérdida progresiva de fuerza en los miembros inferiores con espasticidad. Esto se debe a una lesión axonal en los haces corticoespinales. La de tipo 1, conocida como SPG1, es la forma más común de PEH ligada al cromosoma X. Ésta se produce por una mutación en el gen de la molécula de adhesión celular L1 (L1CAM). La SPG1 se manifiesta con el síndrome CRASH (corpus callosum hypoplasia, retardation, adducted thumbs, spasticity and hydrocephalus). Casos clínicos. Tres varones, dos hermanos y un primo (materno), con un cuadro clínico de discapacidad intelectual, paraparesia espástica, piramidalismo, dismorfias faciales y pulgares en aducción. La neuroimagen mostró agenesia del cuerpo calloso y ventriculomegalia en los tres. Los estudios neurofisiológico y metabólico fueron normales. El estudio genético evidenció en todos ellos una mutación concreta en el gen L1CAM (Xq28). Conclusión. Se describen los hallazgos clinicorradiológicos de tres varones afectos de síndrome CRASH por mutación c.516G>A en el exón 5 del gen L1CAM. Éstos parecen ser los primeros casos descritos en España según la bibliografía actual. Recomendamos sospechar este síndrome cuando se asocian paraparesia espástica, discapacidad intelectual y pulgares aductos

Introduction. Hereditary spastic paraplegia (HSP) is a set of neurodegenerative clinical features characterised by a progressive loss of strength in the lower limbs together with spasticity. It is the result of an axonal lesion in the corticospinal tracts. Type 1, known as SPG1, is the most common form of X-linked HSP. This is produced by a mutation in the gene for the L1 cell adhesion molecule (L1CAM). SPG1 presents with CRASH syndrome (corpus callosum hypoplasia, retardation, adducted thumbs, spasticity and hydrocephalus). Case reports. We report the cases of three males, two brothers and a cousin (on the mother’s side), with clinical features including intellectual disability, spastic paraparesis, long tract signs, facial dysmorphism and adducted thumbs. Neuroimaging revealed agenesis of the corpus callosum and ventriculomegaly in all three of them. Neurophysiological and metabolic studies were normal. The genetic study evidenced a specific mutation of the L1CAM gene (Xq28) in all three cases. Conclusion. We describe the clinical-radiological findings in three males with CRASH syndrome due to mutation c.516G>A in exon 5 of the L1CAM gene. These seem to be the first cases reported in Spain, according to the current literature. We recommend suspecting this syndrome when spastic paraparesis, intellectual disability and adducted thumbs are associated