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RATIONALE: Skeletal dysplasias are a complex series of rare genetic disorders that cause irregular development of bones, joints, and cartilages in children. A total of 770 disorders associated with 41 groups of skeletal dysplasia have been documented, demonstrating a wide range of clinical manifestations and varying levels of severity. In addition to conventional methods, whole genome sequencing has emerged as a useful approach to pinpointing the underlying etiology of skeletal dysplasias. PATIENT CONCERNS: A 13-month-old female was admitted to the hospital due to the symptoms of jaundice and failure to thrive. DIAGNOSES: The child was subjected to blood tests and a radiographic assessment. The blood chemistries revealed elevated levels of total bilirubin (178 µmol/L), bile acids (198 µmol/L), and low levels of serum calcium (1.69 mmol/L) and phosphate (0.8 mmol/L), along with irregular skeletal development in the forearms and legs, considering rickets and cholestasis. INTERVENTIONS: Whole exome sequencing data of the proband revealed a homozygous mutation of c.388dupA in the BAAT (bile acid-CoA: amino acid N-acyltransferase) gene sequence. This mutation caused a frameshift in the amino acid of the BAAT protein, resulting in the pR130Kfs*12 variant. This mutation has been identified as the underlying cause of skeletal dysplasia in the proband. OUTCOMES: A novel frameshift mutation in the BAAT gene of a Vietnamese female child diagnosed with skeletal dysplasia has been studied by whole exome sequencing analysis. LESSONS: This research reported a case of skeletal dysplasia caused by a frameshift mutation in the BAAT gene. The results of this study contribute to our understanding of the diverse factors that influence irregular skeletal development in children and provide genetic data to support clinical practice.

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RATIONALE: Pantothenate kinase-associated neurodegeneration (PKAN), also called Hallervorden-Spatz syndrome, is a rare autosomal recessive disease associated with brain iron accumulation and characterized by progressive dystonia, dementia, and dysarthria symptoms. PKAN, caused by a defective pantothenate kinase 2 (PANK2) gene, is the most common neurodegeneration with a brain iron accumulation (NBIA) group. The "eye of the tiger" sign in the magnetic resonance imaging demonstrated a bilateral hyperintense signal in the basal ganglia region on T2-weighted images, which is a characteristic feature of the diagnosis. PKAN is classified into 2 main types. The early-onset type (classic type) with rapid progression is characterized by symptoms of gait impairment and dystonia leading to loss of ambulation in early childhood. In the later-onset type (atypical type), slow progression usually takes place in the second decade of life with symptoms of neurodegeneration, dystonia, dysarthria, rigidity, choreoathetosis, and motor impairment. Until now, PKAN patients have only been reported in a few countries in Asia such as China, Korea, India, Iran, Taiwan, and Thailand. PATIENT CONCERNS: Here we report the first case of PKAN in Vietnam. The patient had a late onset but the disease progresses rapidly with symptoms of dyskinesia, dysphagia, and difficulty speaking. DIAGNOSES: Pantothenate kinase-associated neurodegeneration. INTERVENTIONS: Whole exome sequencing was performed to identify heterozygous mutations in the PANK2 gene (NM_153638.4) (c.856C>T, p.Arg286Cys and c.1351C>T, p.Arg451Ter) that has been confirmed as the cause of the disease. OUTCOMES: In this study, the first Vietnamese patient with late-onset PKAN was diagnosed by the whole exome sequencing method. LESSONS: The patient's case marks an important milestone for the first case in Vietnam. The results of the study will provide a scientific basis for clinicians in the diagnosis and genetic counseling of patients.

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Limb-girdle muscular dystrophy-type 2C (LGMD2C) is caused by mutations in the SGCG gene. Here, we report a case of a 26-year-old male who had inactive walking due to proximal muscle weakness. Targeted next-generation sequencing found a novel variant c.412C > T (Q138*) in the SGCG gene.

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OBJECTIVES: The 5α-reductase-type-2 deficiency (5ARD2) is a rare autosomal recessive 46,XY disorder of sex development caused by the mutated 5α-reductase type 2 (SRD5A2) gene. In this disease, defective conversion of testosterone to dihydrotestosterone leads to variable presentations of male ambiguous genitalia during fetal development. We aimed to examine characteristics of patients presenting with 5ARD2 over a 4 year period. METHODS: Random urine samples of control and patients with suspected 5ARD2 were collected and urine steroidomic metabolites were measured by Gas chromatography-mass spectrometry (GC-MS) in the period from 2017 to 2021 at National Children's Hospital, Hanoi Vietnam. 5α- to 5ß-reduced steroid metabolite ratio, 5a-tetrahydrocortisol to tetrahydrocortisol (5α-THF/THF), was reviewed by receive operator characteristics (ROC) curve analysis. Molecular testing was offered to 25 patients who were diagnosed with 5ARD2 by GC-MS urinary steroid analysis. RESULTS: Urine steroidomic profiling was conducted for 104 male controls and 25 patients between the ages of 6 months and 13 years old. Twelve of the twenty-five 5ARD2 patients agreed to undertake genetic analysis, and two mutations of the SRD5A2 gene were detected in each patient, confirming the diagnosis. All patients showed a characteristically low ratio of 5α-THF/THF. There was no overlap of 5α-THF/THF ratio values between control and 5ARD2 groups. The ROC of 5α-THF/THF ratio at 0.19 showed 100% sensitivity and 100% specificity for boys between 6 months and 13 years of age. CONCLUSIONS: Analysis of the urine steroid metabolome by GC-MS can be used to assist in the diagnosis of 5ARD2. We recommend consideration of random urine steroid analysis as a first-line test in the diagnosis of 5ARD2.

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BACKGROUND: Family genetic testing of patients newly diagnosed with a rare genetic disease can improve early diagnosis of family members, allowing patients to receive disease-specific therapies when available. Fabry disease, an X-linked lysosomal storage disorder caused by pathogenic variants in GLA, can lead to end-stage renal disease, cardiac arrhythmias, and stroke. Diagnostic delays are common due to the rarity of the disease and non-specificity of early symptoms. Newborn screening and screening of at-risk populations, (e.g., patients with hypertrophic cardiomyopathy or undiagnosed nephropathies) can identify individuals with Fabry disease. Subsequent cascade genotyping of family members may disclose a greater number of affected individuals, often at younger age than they would have been diagnosed otherwise. METHODS: We conducted a literature search to identify all published data on family genetic testing for Fabry disease, and discussed these data, experts' own experiences with family genetic testing, and the barriers to this type of screening that are present in their respective countries. RESULTS: There are potential barriers that make implementation of family genetic testing challenging in some countries. These include associated costs and low awareness of its importance, and cultural and societal issues. Regionally, there are barriers associated with population educational levels, national geography and infrastructures, and a lack of medical geneticists. CONCLUSION: In this review, the worldwide experience of an international group of experts of Fabry disease highlights the issues faced in the family genetic testing of patients affected with rare genetic diseases.

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BACKGROUND: Primordial dwarfism (PD) is a group of genetically heterogeneous disorders related to developmental disabilities occurring in the uterus and prolongs during all stages of life, resulting in short stature, facial deformities and abnormal brain. OBJECTIVE: To determine the exact cause of the disease in two Vietnamese patients priory diagnosed with PD by severe pre-and postnatal growth retardation with marked microcephaly and some bone abnormalities. METHODS: Whole-exome sequencing was performed for the two patients and mutations in genes related to PD were screened. Sanger sequencing was applied to examine the mutations in the patients of their families. RESULTS: Three novel mutations in the PCNT gene which have not been reported previously were identified in the two patients. Of which, two frameshift mutations (p.Thr479Profs*6 and p.Glu2742Alafs*8) were detected in patient I and one stop-gained mutation (p.Gln1907*) was detected in the patient II. These mutations may result in a truncated PCNT protein, leading to an inactivated PACT domain corresponding to residue His3138-Trp3216 of PCNT protein. Therefore, the three mutations may cause a deficiency of protein functional activity and result in the phenotypes of primordial dwarfism in the two patients. CONCLUSIONS: Clinical presentations in combination with genetic analyses supported an accurate diagnosis of the two patients with microcephalic osteodysplastic primordial dwarfism type II (MOPD II). In addition, these results have important implications for prenatal genetic screening and genetic counseling for the families.

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Muscular dystrophies are a group of heterogeneous clinical and genetic disorders. Two siblings presented with characteristics like muscular dystrophy, abnormal white matter, and elevated serum creatine kinase level. The high throughput of whole exome sequencing (WES) makes it an efficient tool for obtaining a precise diagnosis without the need for immunohistochemistry. WES was performed in the two siblings and their parents, followed by prioritization of variants and validation by Sanger sequencing. Very rare variants with moderate to high predicted impact in genes associated with neuromuscular disorders were selected. We identified two pathogenic missense variants, c.778C>T (p.H260Y) and c.2987G>A (p.C996Y), in the LAMA2 gene (NM_000426.3), in the homozygous state in two siblings, and in the heterozygous state in their unaffected parents, which were confirmed by Sanger sequencing. Variant c.2987G>A has not been reported previously. These variants may lead to a change in the structure and function of laminin-α2, a member of the family of laminin-211, which is an extracellular matrix protein that functions to stabilize the basement membrane of muscle fibers during contractions. Overall, WES enabled an accurate diagnosis of both patients with LAMA2-related muscular dystrophy and expanded the spectrum of missense variants in LAMA2.

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Cornelia de Lange Syndrome (CdLS) is a rare congenital genetic disease causing abnormal unique facial phenotypes, several defects in organs and body parts, and mental disorder or intellectual disorder traits. Main causes of CdLS have been reported as variants in cohesin complex genes, in which mutations in the NIPBL gene have been estimated to account for up to 80%. Our study included three Vietnamese patients with typical CdLS phenotypes. Whole exome sequencing revealed two known heterozygous mutations c.6697G>A (p.Val2233Met) and c.2602C>T (p.Arg868X), and a novel heterozygous mutation c.4504delG (p.Val1502fsX87) in the NIPBL gene of the three patients. In silico analyses of the identified mutations predicted possible damaging and truncating effects on the NIPBL protein. Inherited analyses in the patients' families showed that all of the mutations are de novo. Our results lead a definitive diagnosis of patients with CdLS and expand the spectrum of mutations in the NIPBL gene. These findings also confirm whole exome sequencing is an efficient tool for genetic screening of CdLS.

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Inactivating mutations of the CYP21A2 gene, encoding for steroid synthesis, have been reported in patients with congenital adrenal hyperplasia (CAH). We report a case of an infant who were diagnosed with CAH and presented with the severe phenotype of CAH with symptoms such as increased testicular volume, elevated of 17-hydroxyprogesteron, testosterone and progesterone. In this study, we established an assay for the detection of unusual genetic in the CYP21A2 gene in the proband and his family. A novel nonsense mutation c.374C > G which caused a substitutions of Serine for a stop codon at codon 125 (p.S125*) within exon 3 was found in the proband. Parental genotype studies confirmed carrier state in the father, but the mother showed a wild allele by PCR and sequencing. This inspired us to find deletions using multiplex ligation-dependent probe amplification (MLPA) technique. The probands were found to have a large deletion in exons 1 and 3, while the mother only had deletion in exon 1. Therefore, mutation c.374C > G (p.S125*) in the proband is considered as a heterozygous deletion. This mutation caused a truncated protein which lead to the salt wasting CAH phenotype of the proband. This novel nonsense mutation expands the CYP21A2 mutation spectrum in CAH disorder. This case also highlights the need of caution when interpreting results of molecular genetic testing during genetic counseling.

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Introduction: 11ß-hydroxylase deficiency is the second most common form of congenital adrenal hyperplasia (CAH), accounting for 5-8% of all cases. It is an autosomal recessive enzyme defect that impairs the biosynthesis of cortisol and aldosterone. Mutation of the CYP11B1 gene on chromosome 8q22 causes partial or total reduction of enzyme activity. Clinical manifestations of 11ß-hydroxylase deficiency include hypertension, and other signs related to overproduction of mineralocorticoids, and virilisation. Here, we report on a case of 11ß-hydroxylase deficiency detected by urine steroid metabolome profiling. Case Subject: The patient, a 3-month-old male, suffered from truncus arteriosus type I (congenital cardiovascular anomaly) and also presented with hyperpigmentation. An endocrinology consultation was sought and biochemical and molecular testing was conducted. Results: The patient's urine steroid metabolome, as analysed by GC-MS, showed high excretion of tetrahydrodeoxycortisol (THS) and a THS/(THE + THF + 5αTHF) ratio of 2.3, which was higher than normal. Diagnosis of 11ß-hydroxylase deficiency was confirmed by mutation analysis of the CYP11B1 gene. Conclusion: Analysis of the urine steroid metabolome by GC-MS can be used to assist in diagnosis of 11ß-hydroxylase deficiency. We recommend consideration of urine steroid analysis as a first-line test in the diagnosis of CAH.

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Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease which is characterized by a deficiency of one of the enzymes involved in the synthesis of cortisol from cholesterol by the adrenal cortex. CAH cases arising from impaired 11ß-hydroxylase are the second most common form. Mutations in the CYP11B1 gene are the cause of 11ß-hydroxylase deficiency. This study was performed on a patient with congenital adrenal hyperplasia and with premature development such as enlarged penis, muscle development, high blood pressure, and bone age equivalent of 5 years old at 2 years of chronological age. Biochemical tests for steroids confirmed the diagnosis of CAH. We used PCR and sequencing to screen for mutations in CYP11B1 gene. Results showed that the patient has a novel homozygous mutation of guanine (G) to thymine (T) in intron 6 (IVS6+5G>T). The analysis of this mutation by MaxEntScan boundary software indicated that this mutant could affect the gene splicing during transcription.

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CONTEXT: The deficiency of steroid 11ß-hydroxylase is caused by mutations in the CYP11B1 gene and is the second major form of congenital adrenal hyperplasia associated with hypertension. OBJECTIVE: The objective of this study was to screen the CYP11B1 gene for mutations in one Vietnamese male suffering from congenital adrenal hyperplasia. PATIENT: The patient (46,XY) had congenital adrenal hyperplasia. The clinical manifestations presented precocious puberty, hyper-pigmentation and high blood pressure at 4 years. RESULTS: The patient was a homozygous carrier of a novel mutation located in exon 7 containing a premature stop codon instead of tyrosine at 395 (p.Y395X). CONCLUSION: We have identified a novel mutant of the CYP11B1 gene in one Vietnamese family associated with phenotypes of congenital adrenal hyperplasia. The mutant gene p.Y395X produces a truncated form of the polypeptide and abolishes the enzyme activities, leading to a severe phenotype of congenital adrenal hyperplasia.

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The SMN1 and NAIP genes are related to the development of spinal muscular atrophy (SMA), which is characterized by degeneration of motor neurons leading to progressive muscular weakness and atrophy. The SMN1 gene is homozygously deleted in most SMA patients, and now recognized as a responsible gene for SMA. The NAIP gene is often deleted in the SMA patients with the severest form of SMA, and now considered to be a modifying factor of the severity of SMA. Our previous study of five Vietnamese SMA patients showed that the SMN1 gene deletion was detected in one patient, although the NAIP gene deletion was not detected in any patients. In this study, we analyzed 12 Vietnamese SMA patients who were not enrolled in the previous study. The SMN1 gene was homozygously deleted in six out of 12 patients, and the NAIP gene deletion was detected in five patients. Taken together with our previous data, the SMN1 gene deletion was detected in seven out of 17 Vietnamese SMA patients and the NAIP gene deletion in five out of 17 Vietnamese SMA patients. These studies suggest that the SMN1 and NAIP gene deletions are not rare in Vietnamese SMA patients. Thus, the confirmation of SMA-related gene deletion will also be a useful tool for the diagnosis of SMA in Vietnam.

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