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More than 90% suspected muscular dystrophy (MD) can be confirmed with multiplex ligation-dependent probe amplification (MLPA) combined with targeted panel, although there are a few that cannot be identified. A total of 312 suspected MD patients were enrolled into the study. The MLPA combined with a targeted myopathy panel were performed. Patients with negative results were subjected to whole exome sequencing (WES), whole genome sequencing (WGS), and/or RNA sequencing (RNA-seq). A total of 275 cases were diagnosed as Duchenne/Becker muscular dystrophy (DMD/BMD) and 20 cases were other types of myopathy or nonmuscular diseases. Six female DMD/BMD patients suffered from varying degrees of typical DMD-like symptoms and 2 others were suspected to be gonadal mosaicism. The systematic application of WES, WGS, and/or RNA-seq highlighted the need for the detection of variants missed by the current standard diagnostic procedures. The identification of female patients and mosaic carriers was crucial to predict the risk of recurrence and allow for optimal genetic counseling.
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Introduction: Hyponatremia is one of the most prevalent water-electrolyte disturbances encountered in clinical practice in pediatrics and can arise from various conditions. However, there are limited reports on hyponatremia in hospitalized infants. The objective of this study was to provide an overview of the incidence, etiologies, and clinical characteristics of hyponatremia in hospitalized babies (from birth to 3 years old) at a tertiary hospital. Method: Computer records of all hospitalized babies (from birth to 3 years old) with hyponatremia were extracted from the First Affiliated Hospital of Guangxi Medical University's clinical databases. Results: 801 patients from 39,019 hospital admissions were found to have hyponatremia and the overall prevalence of this condition was 2.05% in babies. Patients with hyponatremia due to aldosterone signaling abnormalities, neurological disorders, and liver diseases exhibited more severe outcomes than those with other etiologies. Conclusions: Various conditions can result in hyponatremia in hospitalized babies. Aldosterone signaling abnormalities were not that uncommon and it could lead to severe hyponatremia in babies.
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BACKGROUND: Emery-Dreifuss muscular dystrophy (EDMD2) is a rare form of muscular dystrophy that is inherited as an autosomal dominant trait. In some patients, it is inherited from parental mosaicism, and this increases the recurrence risk significantly. The presence of mosaicism is underestimated due to the limitations of genetic testing and the difficulty in obtaining samples. METHODS: A peripheral blood sample from a 9-year-old girl with EDMD2 was analyzed by enhanced whole exome sequencing (WES). Sanger sequencing in her unaffected parents and younger sister was performed for validation. In the mother, ultra-deep sequencing and droplet digital PCR (ddPCR) in multiple samples (blood, urine, saliva, oral epithelium, and nail clippings) were performed in order to identify the suspected mosaicism of the variant. RESULTS: WES revealed a heterozygous mutation (LMNA, c.1622G>A) in the proband. Sanger sequencing of the mother suggested the presence of mosaicism. The ratio of mosaic mutation was confirmed in different samples by ultra-deep sequencing and ddPCR (19.98%-28.61% and 17.94%-28.33%, respectively). This inferred that the mosaic mutation may have occurred early during embryonic development and that the mother had gonosomal mosaicism. CONCLUSION: We described a case of EDMD2 caused by maternal gonosomal mosaicism which was confirmed by using ultra-deep sequencing and ddPCR. This study illustrates the importance of a systematic and comprehensive screening of parental mosaicism with more sensitive approaches and the use of multiple tissue samples.
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Mosaicismo , Distrofia Muscular de Emery-Dreifuss , Humanos , Femenino , Niño , Distrofia Muscular de Emery-Dreifuss/genética , Mutación , Reacción en Cadena de la Polimerasa , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
Introduction: Hyperkalemia is a rare but severe condition in young children and usually discovered as a result of hemolysis of the blood samples taken. However, patients with defects in either aldosterone biosynthesis or function can also present with hyperkalemia- as well hyponatremia-associated, and metabolic acidosis. It is a challenge to make an accurate diagnosis of these clinical conditions. We conducted this study to investigate the clinical and genetic features of aldosterone signaling defects associated hyperkalemia in young children. Method: A retrospective review was conducted at the pediatric department of the First Affiliated Hospital of Guangxi Medical University from 2012 to 2022. Results: 47 patients with hyperkalemia were enrolled, of which 80.9% (n = 38) were diagnosed with primary hypoaldosteronism, including congenital adrenal hyperplasia due to 21-hydroxylase deficiency (n = 32), isolated hypoaldosteronism (n = 1) due to CYP11B2 gene mutation and Xp21 contiguous gene deletion syndrome (n = 1). Additionally, 4 patients were clinically-diagnosed with primary adrenal insufficiency. Nine patients were confirmed with aldosterone resistance, of which one child was diagnosed with pseudohypoaldosteronism (PHA) type 1 with a mutation in the NR3C2 gene and 3 children were identified with PHA type 2 due to novel mutations in either the CUL3 or KLHL3 genes. Five patients had PHA type 3 because of pathologies of either the urinary or intestinal tracts. Conclusions: The etiologies of infants with hyperkalemia associated with aldosterone defects were mostly due to primary hypoaldosteronism. An elevated plasma aldosterone level may be a useful biomarker for the diagnosis an aldosterone functional defect in patients presented with hyperkalemia. However, a normal plasma aldosterone level does rule out an aldosterone defect in either its biosynthesis or function, especially in young infants. Molecular genetic analyses can greatly help to clarify the complexity of disorders and can be used to confirm the diagnosis.
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OBJECTIVES: To summarize the skeletal muscle magnetic resonance imaging (MRI) features of the lower limbs in common subtypes of muscular dystrophy (MD) and the experience in the application of MRI in the diagnosis of MD. METHODS: A total of 48 children with MD who were diagnosed by genetic testing were enrolled as subjects. The muscle MRI features of the lower limbs were analyzed. Cumulative fatty infiltration score was calculated for each subtype, and the correlation of cumulative fatty infiltration score with clinical indices was analyzed for Duchenne muscular dystrophy (DMD). RESULTS: DMD was characterized by the involvement of the gluteus maximus and the adductor magnus. Becker muscular dystrophy was characterized by the involvement of the vastus lateralis muscle. Limb-girdle muscular dystrophy was characterized by the involvement of the adductor magnus, the vastus intermedius, the vastus medialis, and the vastus lateralis muscle. For DMD, the cumulative fatty infiltration score of the lower limb muscles was significantly correlated with age, course of the disease, muscle strength, and motor function (P<0.05), while it was not significantly correlated with the serum creatine kinase level (P>0.05). CONCLUSIONS: Different subtypes of MD have different MRI manifestations, and MRI may help with the diagnosis and assessment of MD.
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Distrofia Muscular de Cinturas , Distrofia Muscular de Duchenne , Niño , Humanos , Distrofia Muscular de Duchenne/diagnóstico por imagen , Distrofia Muscular de Cinturas/diagnóstico por imagen , Distrofia Muscular de Cinturas/patología , Músculo Esquelético/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Muslo/patologíaRESUMEN
Bethlem myopathy (BM) is an autosomal dominant or autosomal recessive disorder and is usually associated with mutations in the collagen VI genes. In the present study, the pathogenicity of a novel splicesite mutation was explored using RNAsequencing in a family with suspected BM, and a myopathy panel was performed in the proband. The genetic status of all family members was confirmed using Sanger sequencing. Clinical data and magnetic resonance imaging (MRI) features were also documented. In silico analysis was performed to predict the effects of the splice mutation. RNAsequencing and reverse transcription (RT)PCR were used to assess aberrant splicing. Immunocytochemistry was conducted to measure collagen VI protein levels within the gastrocnemius and in cultured skin fibroblasts. The results revealed that three patients in the family shared a similar classic BM presentation. MRI revealed distinct patterns of fatty infiltration in the lower extremities. A novel splicing mutation c.7361G>C in the collagen α2 (VI) chain (COL6A2) gene was found in all three patients. In silico analysis predicted that the mutation would destroy the normal splice acceptor site. RNAsequencing detected two abnormal splicing variants adjacent to the mutation site, and RTPCR confirmed the RNAsequencing findings. Furthermore, a defect in the collagen protein within cultured fibroblasts was detected using immunocytochemistry. The mutation c.7361G>C in the COL6A2 gene caused aberrant splicing and led to premature termination of protein translation. In conclusion, these findings may improve our knowledge of mutations of the COL6A2 gene associated with BM and demonstrated that RNAsequencing can be a powerful tool for finding the underlying mechanism of a diseasecausing mutations at a splice site.
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Colágeno Tipo VI , Contractura , Distrofias Musculares/congénito , Mutación Puntual , Sitios de Empalme de ARN , RNA-Seq , Transcripción Genética , Adolescente , Adulto , Colágeno Tipo VI/biosíntesis , Colágeno Tipo VI/genética , Contractura/genética , Contractura/metabolismo , Humanos , Masculino , Distrofias Musculares/genética , Distrofias Musculares/metabolismoRESUMEN
The present study aimed to determine the genetic status of manifesting carriers (MCs) of Duchenne muscular dystrophy (DMD)/Becker muscular dystrophy (BMD) and asymptomatic carriers with a family history of DMD/BMD, and identify potential simple and reliable methods for screening dystrophinopathy carriers. Clinical data from probable carriers and MCs were collected and analyzed. MCs underwent multiplex ligationdependent probe amplification (MLPA) for dystrophin gene exons combined with muscle disease panel test based on a nextgeneration sequencing (NGS) platform. In addition, the status of probable carriers was determined by MLPA or Sanger sequencing, according to the mutations of probands. A total of 154 female were enrolled, among which 78 cases were found to be carriers, including 4 MCs and 74 asymptomatic female carriers. The 4 MCs exhibited duplication mutations. Among the 74 asymptomatic carriers, 41.89% harbored deletion mutations, including 2 cases with suspected germline mosaicism and no mutation in the dystrophin gene, while 44.59% harbored point mutations in exons and only 10 cases (13.51%) carried duplication mutations. The area under the receiver operating characteristic (ROC) curve of creatine kinase (CK) was 0.822, with a sensitivity of 65.38% and specificity of 92.1%. In addition, DMD was positively correlated with the CK, alanine transaminase and aspartate transaminase levels of the carriers. MLPA for exons of the dystrophin gene, along with NGS and Sanger sequencing, was effective for the diagnosis of MCs and for determining the status of probable carriers. The ROC curve analysis also demonstrated that CK level was an excellent predictor for distinguishing DMD/BMD carriers.
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Distrofina/genética , Estudios de Asociación Genética , Heterocigoto , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/genética , Fenotipo , Alelos , Sustitución de Aminoácidos , Biomarcadores , Biopsia , Exones , Femenino , Humanos , Mutación , Curva ROC , Factores Sexuales , Evaluación de SíntomasRESUMEN
This article reported the clinical features of one child with infantile hypophosphatasia (HPP) and his pedigree information. The proband was a 5-month-old boy with multiple skeletal dysplasia (koilosternia, bending deformity of both radii, and knock-knee deformity of both knees), feeding difficulty, reduction in body weight, developmental delay, recurrent pneumonia and respiratory failure, and a significant reduction in blood alkaline phosphatase. Among his parents, sister, uncle, and aunt (other family members did not cooperate with us in the examination), his parents and aunt had a slight reduction in alkaline phosphatase and his aunt had scoliosis; there were no other clinical phenotypes or abnormal laboratory testing results. His ALPL gene mutation came from c.228delG mutation in his mother and c.407G>A compound heterozygous mutation in his father. His aunt carried c.228delG mutation. The c.407G>A mutation had been reported as the pathogenic mutation of HPP, and c.228delG mutation was a novel pathogenic mutation. Hypophosphatasia is caused by ALPL gene mutation, and ALPL gene detection is an effective diagnostic method. This study expands the mutation spectrum of ALPL gene and provides a theoretical basis for genetic diagnosis of this disease.