RESUMEN
HOMG1 (hypomagnesemia 1, intestinal) or hypomagnesemia with secondary hypocalcemia is a rare autosomal recessive disorder of magnesium metabolism, characterized by impaired magnesium absorption. This disorder may mimic other conditions presenting with neonatal seizures. Here, we report an infant diagnosed to have hypomagnesemia with secondary hypocalcemia due to novel variants in TRPM6 gene.
RESUMEN
Congenital adrenal hyperplasia (CAH), screened for in neonates, is the second most common endocrinopathy after congenital hypothyroidism.Newborn screening for CAH due to CYP21A2 deficiency is performed by immunologic assay for 17-hydroxyprogesterone (17-OHP). The second-tier test for confirmation of diagnosis is carried out on recall venous blood sample from screen positives measuring 17-OHP, or other metabolites of steroid metabolism by liquid chromatography-tandem mass spectroscopy. However, as steroid metabolism is dynamic, it can affect these parameters even in the recall sample of a stressed neonate. Moreover, there is some time delay in recalling the neonate for repeat testing. Reflex genetic analysis of blood spot from the initial Guthrie cards of screen positive neonates, if used for confirmatory testing, can avoid this time delay as well as the effect of stress on steroid metabolism. In this study, we used Sanger sequencing and MLPA in a reflex manner for molecular genetic analysis to confirm CYP21A2-mediated CAH. Out of 220,000 newborns screened, 97 were positive on the initial biochemical screen, of which 54 were confirmed true positives with genetic reflex testing, giving incidence of CAH as 1:4074. Point mutations were more common than deletions, indicating that Sanger sequencing should be used ahead of MLPA for molecular diagnosis in India. Amongst the variants detected, the most common was I2G-Splice variant (44.5%), followed by c.955C>T (p.Gln319Ter) (21.2%); Del 8 bp and c.-113G>A were detected with frequencies of 20.3% and 20%, respectively. In conclusion, reflex genetic testing is an effective strategy for identifying true positives in CAH screening in neonates. This will obviate need for recall samples and also aid effective counselling and timely prenatal diagnosis in the future. In Indian newborns, as point mutations are more common than large deletions, Sanger sequencing should be the initial method of choice for genotyping, ahead of MLPA.
RESUMEN
Genetic diagnosis depends on having available tissue to test. This can be important for many reasons, such as related to familial diagnosis in the case of another pregnancy. When blood or DNA samples from affected family members are not available, accurate prenatal diagnosis may be much more difficult and hence additional effort may be needed to obtain a genetic diagnosis in such families. We report two families with suspected monogenic disorders where attempts were made to establish the genetic etiology in deceased offspring using dried umbilical cord remnants which had been preserved by the family.
Asunto(s)
Discapacidades del Desarrollo/patología , Hepatopatías/patología , Glicoproteínas de Membrana/genética , Hipotonía Muscular/patología , Mutación , Infecciones del Sistema Respiratorio/patología , Cordón Umbilical/química , alfa-Glucosidasas/genética , Discapacidades del Desarrollo/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Lactante , Hepatopatías/genética , Masculino , Hipotonía Muscular/genética , Embarazo , Diagnóstico Prenatal/métodos , Infecciones del Sistema Respiratorio/genéticaRESUMEN
The analysis of individuals with severe congenital neutropenia (SCN) may shed light on the delicate balance of factors controlling the differentiation, maintenance and decay of neutrophils. We identify 9 distinct homozygous mutations in the JAGN1 gene encoding Jagunal homolog 1 in 14 individuals with SCN. JAGN1-mutant granulocytes are characterized by ultrastructural defects, a paucity of granules, aberrant N-glycosylation of multiple proteins and increased incidence of apoptosis. JAGN1 participates in the secretory pathway and is required for granulocyte colony-stimulating factor receptor-mediated signaling. JAGN1 emerges as a factor that is necessary in the differentiation and survival of neutrophils.
Asunto(s)
Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Células Mieloides/metabolismo , Neutropenia/congénito , Adolescente , Adulto , Apoptosis/genética , Diferenciación Celular/genética , Supervivencia Celular/genética , Niño , Preescolar , Síndromes Congénitos de Insuficiencia de la Médula Ósea , Femenino , Glicosilación , Homeostasis/genética , Humanos , Lactante , Recién Nacido , Masculino , Proteínas de la Membrana/metabolismo , Mutación , Neutropenia/genética , Neutropenia/metabolismo , Neutropenia/patología , Neutrófilos/metabolismo , Receptores de Factor Estimulante de Colonias de Granulocito/genética , Receptores de Factor Estimulante de Colonias de Granulocito/metabolismo , Transducción de Señal , Adulto JovenRESUMEN
We describe a novel clinical phenotype associating T- and B-cell lymphopenia, intermittent neutropenia, and atrial septal defects in 3 members of a consanguineous kindred. Their clinical histories included recurrent bacterial infections, viral infections, mucocutaneous candidiasis, cutaneous warts, and skin abscesses. Homozygosity mapping and candidate gene sequencing revealed a homozygous premature termination mutation in the gene STK4 (serine threonine kinase 4, formerly having the symbol MST1). STK4 is the human ortholog of Drosophila Hippo, the central constituent of a highly conserved pathway controlling cell growth and apoptosis. STK4-deficient lymphocytes and neutrophils exhibit enhanced loss of mitochondrial membrane potential and increased susceptibility to apoptosis. STK4 deficiency is a novel human primary immunodeficiency syndrome.
Asunto(s)
Síndromes de Inmunodeficiencia/genética , Neutropenia/genética , Proteínas Serina-Treonina Quinasas/genética , Secuencia de Bases , Estudios de Casos y Controles , Preescolar , Consanguinidad , Análisis Mutacional de ADN , Femenino , Humanos , Síndromes de Inmunodeficiencia/sangre , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/inmunología , Péptidos y Proteínas de Señalización Intracelular , Irán/epidemiología , Masculino , Neutropenia/sangre , Neutropenia/etiología , Neutropenia/inmunología , Linaje , Fenotipo , Proteínas Serina-Treonina Quinasas/deficienciaRESUMEN
Biallelic mutations in the gene encoding HCLS-associated protein X-1 (HAX1) cause autosomal recessive severe congenital neutropenia (SCN). Some of these patients have neurological abnormalities including developmental delay, cognitive impairment, and/or epilepsy. Recent genotype-phenotype studies have shown that mutations in HAX1 affecting transcripts A (NM_006118.3) and B (NM_001018837.1) cause the phenotype of SCN with neurological impairment, while mutations affecting isoform A but not B lead to SCN without neurological aberrations. In this study, we identified a consanguineous family with two patients suffering from SCN and neurological disease caused by a novel, homozygous genomic deletion including exons 4-7 of the HAX1 gene. Quantitative MRI analyses showed generalized alterations in cerebral proton density in both of the patients, as well as in an additional unrelated patient with another HAX1 mutation (Arg86X) known to be associated with neurological manifestations. This study provides first in vivo evidence of aberrant neuroimaging findings associated with HAX1 deficiency in SCN patients.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Encéfalo/anomalías , Mutación , Enfermedades del Sistema Nervioso/genética , Neutropenia/congénito , Neutropenia/genética , Adulto , Estudios de Casos y Controles , Niño , Consanguinidad , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/genética , Epilepsia/complicaciones , Epilepsia/congénito , Epilepsia/genética , Femenino , Genes Recesivos , Homocigoto , Humanos , Imagen por Resonancia Magnética/métodos , Enfermedades del Sistema Nervioso/complicaciones , Enfermedades del Sistema Nervioso/congénito , Enfermedades del Sistema Nervioso/patología , Neutropenia/complicaciones , Linaje , Fenotipo , Isoformas de Proteínas/genética , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: The main features of severe congenital neutropenia are the onset of severe bacterial infections early in life, a paucity of mature neutrophils, and an increased risk of leukemia. In many patients, the genetic causes of severe congenital neutropenia are unknown. METHODS: We performed genomewide genotyping and linkage analysis on two consanguineous pedigrees with a total of five children affected with severe congenital neutropenia. Candidate genes from the linkage interval were sequenced. Functional assays and reconstitution experiments were carried out. RESULTS: All index patients were susceptible to bacterial infections and had very few mature neutrophils in the bone marrow; structural heart defects, urogenital abnormalities, and venous angiectasia on the trunk and extremities were additional features. Linkage analysis of the two index families yielded a combined multipoint lod score of 5.74 on a linkage interval on chromosome 17q21. Sequencing of G6PC3, the candidate gene encoding glucose-6-phosphatase, catalytic subunit 3, revealed a homozygous missense mutation in exon 6 that abolished the enzymatic activity of glucose-6-phosphatase in all affected children in the two families. The patients' neutrophils and fibroblasts had increased susceptibility to apoptosis. The myeloid cells showed evidence of increased endoplasmic reticulum stress and increased activity of glycogen synthase kinase 3beta (GSK-3beta). We identified seven additional, unrelated patients who had severe congenital neutropenia with syndromic features and distinct biallelic mutations in G6PC3. CONCLUSIONS: Defective function of glucose-6-phosphatase, catalytic subunit 3, underlies a severe congenital neutropenia syndrome associated with cardiac and urogenital malformations.
Asunto(s)
Anomalías Múltiples/genética , Glucosa-6-Fosfatasa/genética , Cardiopatías Congénitas/genética , Mutación Missense , Neutropenia/genética , Anomalías Urogenitales/genética , Adolescente , Apoptosis/genética , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Estudio de Asociación del Genoma Completo , Glucosa-6-Fosfatasa/metabolismo , Enfermedad del Almacenamiento de Glucógeno Tipo I/genética , Humanos , Lactante , Escala de Lod , Masculino , Neutropenia/congénito , Neutropenia/fisiopatología , Neutrófilos/fisiología , Linaje , Síndrome , Telangiectasia/genéticaRESUMEN
Autosomal recessive severe congenital neutropenia (SCN) constitutes a primary immunodeficiency syndrome associated with increased apoptosis in myeloid cells, yet the underlying genetic defect remains unknown. Using a positional cloning approach and candidate gene evaluation, we identified a recurrent homozygous germline mutation in HAX1 in three pedigrees. After further molecular screening of individuals with SCN, we identified 19 additional affected individuals with homozygous HAX1 mutations, including three belonging to the original pedigree described by Kostmann. HAX1 encodes the mitochondrial protein HAX1, which has been assigned functions in signal transduction and cytoskeletal control. Here, we show that HAX1 is critical for maintaining the inner mitochondrial membrane potential and protecting against apoptosis in myeloid cells. Our findings suggest that HAX1 is a major regulator of myeloid homeostasis and underline the significance of genetic control of apoptosis in neutrophil development.