A Novel NR5A1 Mutation in a Thai Boy with 46, XY DSD.

Disorders of sex development (DSD) can be classified as 46,XX DSD, 46,XY DSD, and sex chromosome DSD. Several underlying causes including associated genes have been reported. Steroidogenic factor-1 is encoded by the NR5A1 gene, a crucial regulator of steroidogenesis in the growth of the adrenal and gonadal tissues. It has been discovered to be responsible for 10 to 20% of 46, XY DSD cases. Here, we described a 2-month-old infant who had ambiguous genitalia and 46, XY. Using whole exome sequencing followed by polymerase chain reaction-Sanger sequencing, a novel heterozygous nonsense c.1249C > T (p.Gln417Ter) variant in the NR5A1 gene was identified. It is present in his mother but absent in his father and maternal aunt and uncle. At the age of 7 months, the patient received a monthly intramuscular injection of low-dose testosterone for 3 months in a row. His penile length and diameter increased from 1.8 to 3 cm and from 0.8 to 1.3 cm, respectively. The patient also had normal adrenal reserve function by adrenocorticotropic hormone stimulation test. This study identified a novel causative p.Q417X (c.1249C > T) variant in NR5A1 causing 46,XY DSD in a Thai boy which is inherited from his unaffected mother.

F8 variants and their genotype-phenotype correlations in Thai patients with haemophilia A: a nationwide multicentre study.

AIMS: Analysis of the F8 gene helps predict the risk of developing factor VIII (FVIII) inhibitors and the depth of phenotype in haemophilia A (HA) patients. Since data in Southeast Asian countries remain scarce, we aim to study F8 variation correlated with HA phenotypes in Thailand. METHODS: Thai patients with HA were enrolled from seven haemophilia treatment centres during 2022-2023. Using peripheral blood DNA, inverse shifting-polymerase chain reaction (IS-PCR) for F8-intron 22 inversion (Inv22) and F8-intron 1 inversion (Inv1) was performed. Whole exome sequencing (WES) was explored in cases without Inv22/Inv1. RESULTS: Of 124 patients with HA, 91.9% were detected with a causative F8 variant, including Inv22 (30.6%), Inv1 (1.6%), missense (23.4%), nonsense (16.9%) and small insertion/deletion (16.1%) mutations. Inv22, small insertion/deletion and nonsense were associated with severe HA, compared with missense variants, by the ORs of 13.9 (95% CI, 4.2 to 56.7), 14.7 (95% CI, 3.4 to 104.7) and 15.6 (95% CI, 3.6 to 110.2), respectively. While nonsense variants affecting the light chain increased the risk of developing FVIII inhibitors (OR, 6.8; 95% CI, 1.5 to 32.6) compared with the low-risk (small insertion/deletion, missense and splice-site) variants. Twelve patients (9.7%) harboured novel F8 variants, comprising five missense (p.Pro540Leu, p.Ser564Pro, p.Leu668Pro, p.Ala1721Glu, p.His2024Pro), five small insertion/deletion (p.Val502SerfsTer13, p.Ile522PhefsTer13, p.Phe992LysfsTer11, p.Leu1223PhefsTer18, c.6427_6429+3delATGGTA) and one nonsense mutations (p.Glu1292Ter). CONCLUSIONS: IS-PCR followed by WES successfully assesses F8 alterations in most HA cases. With several unique variants, severe HA in Thailand is considerably caused by Inv22, small insertion/deletion and nonsense, whereas missense variants are more responsible for nonsevere HA phenotypes.

Prevalence and clinical outcomes of germline variants among patients with myeloid neoplasms.

AIMS: Myeloid neoplasms (MNs) with germline predisposition have been recognised as a distinct entity. Emerging evidence suggests that sporadic myelodysplastic syndromes may also harbour undetected germline predispositions. We investigated germline alterations in a cohort of 122 adult Thai MNs. METHODS: MN patients were recruited and tested for germline variants using deep targeted next-generation sequencing. The germline variant was filtered using American College of Medical Genetics classifications and then evaluated for the association with clinical characteristics and outcomes. RESULTS: Our findings revealed pathogenic/likely pathogenic germline alterations in 12 (10%) of the patients. These germline lesions were commonly found in the DNA damage response pathway (n=6, 50%). We also identified novel deleterious FANCA A1219GfsTer59 variants in two patients diagnosed with secondary acute myeloid leukaemia (sAML) from aplastic anaemia and AML with myelodysplasia related. Among sAML, individuals with germline mutations had inferior overall survival compared with those with wild-type alleles (2 months vs 12 months) with HR 4.7 (95% CI 1.0 to 20), p=0.037. Therefore, the presence of pathogenic or likely pathogenic mutations may be linked to inferior survival outcomes. CONCLUSIONS: Our study highlighted that the prevalence of germline predisposition in Southeast Asian populations is comparable to that in Caucasians. This underscores the importance of germline genetic testing within the Asian population.

Genetic variations of type 2 and type 3 von Willebrand diseases in Thailand.

AIMS: Von Willebrand disease (VWD) is an inherited haemostatic disorder with a wide range of bleeding phenotypes based on von Willebrand factor (VWF) levels. Multiple assays including VWF gene analysis are employed to correctly diagnose VWD and its subtypes. However, data on VWF mutations among Southeast Asian populations are lacking. We, therefore, aimed to explore genetic variations in Thai patients with type 2 and type 3 VWD by whole exome sequencing (WES). METHODS: In this multicentre study, Thai patients with type 2 and type 3 VWD, according to the definitions and VWF levels recommended by the international guidelines, were recruited. WES was performed using DNA extracted from peripheral blood in all cases. The novel variants were verified by Sanger sequencing. RESULTS: Fifteen patients (73% females; median age at diagnosis 3.0 years) with type 2 (n=12) and type 3 VWD (n=3) from 14 families were enrolled. All patients harboured at least one VWF variant. Six missense (p.Arg1374Cys, p.Arg1374His, p.Arg1399Cys, p.Arg1597Trp, p.Ser1613Pro, p.Pro1648Arg) and one splice-site (c.3379+1G>A) variants in the VWF gene were formerly described. Notably, six VWF variants, including three missense (p.Met814Ile, p.Trp856Cys, p.Pro2032Leu), one deletion (c.2251delG) and two splice-site (c.7729+4A>C, c.8115+2delT) mutations were novelly identified. Compound heterozygosity contributed to type 2 and type 3 VWD phenotypes in two and one patients, respectively. CONCLUSIONS: Type 2 and type 3 VWD in Thailand demonstrate the mutational variations among VWF exons/introns with several unique variants. The WES-based approach potentially provides helpful information to verify VWD diagnosis and facilitate genetic counselling in clinical practice.

Genetic, metabolic and clinical delineation of an MRPS23-associated mitochondrial disorder.

MRPS23 is a nuclear gene encoding a mitochondrial ribosomal protein. A patient with a mitochondrial disorder was found to carry a variant in MRPS23. More cases are necessary to establish MRPS23 as a mitochondrial disease gene. Of 5134 exomes performed in our center, we identified five independent patients who had similar clinical manifestations and were homozygous for the same germline variant c.119C>T; p.P40L in MRPS23. Detailed clinical findings, mitochondrial enzyme activity assays from cultured skin fibroblasts, PCR-Sanger-sequencing, and variant age estimation were performed. Their available family members were also studied. Eight members homozygous for the MRPS23 p.P40L were identified. All were from Hmong hilltribe. Seven presented with alteration of consciousness and recurrent vomiting, while the eighth who was a younger brother of a proband was found pre-symptomatically. Patients showed delayed growth and development, hearing impairment, hypoglycemia, lactic acidosis, and liver dysfunction. In vitro assays of cultured fibroblasts showed combined respiratory chain complex deficiency with low activities of complexes I and IV. PCR-Sanger-sequencing confirmed the variant, which was estimated to have occurred 1550 years ago. These results establish the MRPS23-associated mitochondrial disorder inherited in an autosomal recessive pattern and provide insight into its clinical and metabolic features.

Nine patients with KCNQ2-related neonatal seizures and functional studies of two missense variants.

Mutations in KCNQ2 encoding for voltage-gated K channel subunits underlying the neuronal M-current have been associated with infantile-onset epileptic disorders. The clinical spectrum ranges from self-limited neonatal seizures to epileptic encephalopathy and delayed development. Mutations in KCNQ2 could be either gain- or loss-of-function which require different therapeutic approaches. To better understand genotype-phenotype correlation, more reports of patients and their mutations with elucidated molecular mechanism are needed. We studied 104 patients with infantile-onset pharmacoresistant epilepsy who underwent exome or genome sequencing. Nine patients with neonatal-onset seizures from unrelated families were found to harbor pathogenic or likely pathogenic variants in the KCNQ2 gene. The p.(N258K) was recently reported, and p. (G279D) has never been previously reported. Functional effect of p.(N258K) and p.(G279D) has never been previously studied. The cellular localization study demonstrated that the surface membrane expression of Kv7.2 carrying either variant was decreased. Whole-cell patch-clamp analyses revealed that both variants significantly impaired Kv7.2 M-current amplitude and density, conductance depolarizing shift in voltage dependence of activation, membrane resistance, and membrane time constant (Tau), indicating a loss-of-function in both the homotetrameric and heterotetrameric with Kv7.3 channels. In addition, both variants exerted dominant-negative effects in heterotetrameric with Kv7.3 channels. This study expands the mutational spectrum of KCNQ2- related epilepsy and their functional consequences provide insights into their pathomechanism.

Pathogenic variant detection rate by whole exome sequencing in Thai patients with biopsy-proven focal segmental glomerulosclerosis.

The spectra of underlying genetic variants for various clinical entities including focal segmental glomerulosclerosis (FSGS) vary among different populations. Here we described the clinical and genetic characteristics of biopsy-proven FSGS patients in Thailand. Patients with FSGS pathology, without secondary causes, were included in our study. Clinical laboratory and pathological data were collected. Whole-exome sequencing (WES) was subsequently performed. 53 unrelated FSGS patients were recruited. 35 patients were adults (66.0%), and 51 patients were sporadic cases (96.2%). Clinical diagnosis before kidney biopsy was steroid-resistant nephrotic syndrome (SRNS) in 58.5%, and proteinuric chronic kidney disease in 32.1%. Using WES, disease-associated pathogenic/likely pathogenic (P/LP) variants could be identified in six patients including the two familial cases, making the P/LP detection rate of 11.3% (6/53). Of these six patients, two patients harbored novel variants with one in the COL4A4 gene and one in the MAFB gene. Four other patients carried previously reported variants in the CLCN5, LMX1B, and COL4A4 genes. Four of these patients (4/6) received immunosuppressive medications as a treatment for primary FSGS before genetic diagnosis. All four did not respond to the medications, emphasizing the importance of genetic testing to avoid unnecessary treatment. Notably, the mutation detection rates in adult and pediatric patients were almost identical, at 11.4% and 11.1%, respectively. In conclusion, the overall P/LP variant detection rate by WES in biopsy-proven FSGS patients was 11.3%. The most identified variants were in COL4A4. In addition, three novel variants associated with FSGS were detected.

Utilisation of exome sequencing for muscular disorders in Thai paediatric patients: diagnostic yield and mutational spectrum.

Muscular dystrophies and congenital myopathies are heterogeneous groups of inherited muscular disorders. An accurate diagnosis is challenging due to their complex clinical presentations and genetic heterogeneity. This study aimed to determine the utilisation of exome sequencing (ES) for Thai paediatric patients with muscular disorders. Of 176 paediatric patients suspected of genetic/inherited myopathies, 133 patients received a molecular diagnosis after performing conventional investigations, single gene testing, and gene panels. The remaining 43 patients from 42 families could be classified into three groups: Group 1, MLPA-negative Duchenne muscular dystrophy (DMD) with 9 patients (9/43; 21%), Group 2, other muscular dystrophies (MD) with 18 patients (18/43; 42%) and Group 3, congenital myopathies (CM) with 16 patients (16/43; 37%). All underwent exome sequencing which could identify pathogenic variants in 8/9 (89%), 14/18 (78%), and 8/16 (50%), for each Group, respectively. Overall, the diagnostic yield of ES was 70% (30/43) and 36 pathogenic/likely pathogenic variants in 14 genes were identified. 18 variants have never been previously reported. Molecular diagnoses provided by ES changed management in 22/30 (73%) of the patients. Our study demonstrates the clinical utility and implications of ES in inherited myopathies.

A germline STAT6 gain-of-function variant is associated with early-onset allergies.

BACKGROUND: The signal transducer and activator of transcription 6 (STAT6) signaling pathway plays a central role in allergic inflammation. To date, however, there have been no descriptions of STAT6 gain-of-function variants leading to allergies in humans. OBJECTIVE: We report a STAT6 gain-of-function variant associated with early-onset multiorgan allergies in a family with 3 affected members. METHODS: Exome sequencing and immunophenotyping of T-helper cell subsets were conducted. The function of the STAT6 protein was analyzed by Western blot, immunofluorescence, electrophoretic mobility shift assays, and luciferase assays. Gastric organoids obtained from the index patient were used to study downstream effector cytokines. RESULTS: We identified a heterozygous missense variant (c.1129G>A;p.Glu377Lys) in the DNA binding domain of STAT6 that was de novo in the index patient's father and was inherited by 2 of his 3 children. Severe atopic dermatitis and food allergy were key presentations. Clinical heterogeneity was observed among the affected individuals. Higher levels of peripheral blood TH2 lymphocytes were detected. The mutant STAT6 displayed a strong preference for nuclear localization, increased DNA binding affinity, and spontaneous transcriptional activity. Moreover, gastric organoids showed constitutive activation of STAT6 downstream signaling molecules. CONCLUSIONS: A germline STAT6 gain-of-function variant results in spontaneous activation of the STAT6 signaling pathway and is associated with an early-onset and severe allergic phenotype in humans. These observations enhance our knowledge of the molecular mechanisms underlying allergic diseases and will potentially contribute to novel therapeutic interventions.

Exome sequencing as first-tier genetic testing in infantile-onset pharmacoresistant epilepsy: diagnostic yield and treatment impact.

Pharmacoresistant epilepsy presenting during infancy poses both diagnostic and therapeutic challenges. We aim to identify diagnostic yield and treatment implications of exome sequencing (ES) as first-tier genetic testing for infantile-onset pharmacoresistant epilepsy. From June 2016 to December 2020, we enrolled patients with infantile-onset (age ≤ 12 months) pharmacoresistant epilepsy. 103 unrelated patients underwent ES. Clinical characteristics and changes in management due to the molecular diagnosis were studied. 42% (43/103) had epilepsy onset within the first month of life. After ES as first-tier genetic testing, 62% (64/103) of the cases were solved. Two partially solved cases (2%; 2/103) with heterozygous variants identified in ALDH7A1 known to cause autosomal recessive pyridoxine dependent epilepsy underwent genome sequencing (GS). Two novel large deletions in ALDH7A1 were detected in both cases. ES identified 66 pathogenic and likely pathogenic single nucleotide variants (SNVs) in 27 genes. 19 variants have not been previously reported. GS identified two additional copy number variations (CNVs). The most common disease-causing genes are SCN1A (13%; 13/103) and KCNQ2 (8%; 8/103). Eight percent (8/103) of the patients had treatable disorders and specific treatments were provided resulting in seizure freedom. Pyridoxine dependent epilepsy was the most common treatable epilepsy (6%; 6/103). Furthermore, 35% (36/103) had genetic defects which guided gene-specific treatments. Altogether, the diagnostic yield is 64%. Molecular diagnoses change management in 43% of the cases. This study substantiates the use of next generation sequencing (NGS) as the first-tier genetic investigation in infantile-onset pharmacoresistant epilepsy.

Genetic diagnosis for adult patients at a genetic clinic.

Clinical utility of genetic testing has rapidly increased in the past decade to identify the definitive diagnosis, etiology, and specific management. The majority of patients receiving testing are children. There are several barriers for genetic tests in adult patients; barriers may arise from either patients or clinicians. Our study aims to realize the detection rate and the benefits of genetic tests in adults. We conducted a prospective study of 10 adult patients who were referred to a genetic clinic. Exome sequencing (ES) was pursued in all cases, and chromosomal microarray (CMA) was performed for six cases. Our result is impressive; six cases (60%) received likely pathogenic and pathogenic variants. Four definitive diagnosis cases had known pathogenic variants in KCNJ2, TGFBR1, SCN1A, and FBN1, whereas another two cases revealed novel likely pathogenic and pathogenic variants in GNB1 and DNAH9. Our study demonstrates the success in genetic diagnosis in adult patients: four cases with definitive, two cases with possible, and one case with partial diagnosis. The advantage of diagnosis is beyond obtaining the diagnosis itself, but also relieving any doubt for the patient regarding any previous questionable diagnosis, guide for management, and recurrence risk in their children or family members. Therefore, this supports the value of genetic testing in adult patients.

TIGIT Monoallelic Nonsense Variant in Patient with Severe COVID-19 Infection, Thailand.

A heterozygous nonsense variant in the TIGIT gene was identified in a patient in Thailand who had severe COVID-19, resulting in lower TIGIT expression in T cells. The patient's T cells produced higher levels of cytokines upon stimulation. This mutation causes less-controlled immune responses, which might contribute to COVID-19 severity.

Severe coarctation of the aorta, developmental delay, and multiple dysmorphic features in a child with SMAD6 and SMARCA4 variants.

Pathogenic variants in SMARCA4 cause Coffin-Siris syndrome (CSS) while those in SMAD6 lead to aortic valve disease and other dysmorphisms. We identified a 6-year-old Thai boy with features of CSS alongside unusual manifestations including, very severe coarctation of the aorta (CoA) requiring coarctectomy in the neonatal period and bilateral radioulnar synostoses. Trio exome sequencing revealed that the patient harbored two de novo variants, a missense c.2475G > T, p.(Trp825Cys) in SMARCA4 and a nonsense c.652C > T, p.(Gln218Ter) in SMAD6. Both of which have never been previously reported. The clinical presentations in our patient are a result of the combinational features of each genetic variant: the SMARCA4 p.(Trp825Cys) variant leads to facial features of Coffin Siris syndrome and Dandy-Walker malformation, while the SMAD6 p.(Gln218Ter) variant underlies radioulnar synostosis. Interestingly, the severity of CoA in the proband is beyond the phenotypic spectra of each genetic variant and may be a result of the synergistic effects of both variants. Here, we report a child with variants in SMARCA4 or SMAD6 with combined features of each plus a severe CoA, possibly due to an additive effect of each variant.

Genetic basis of sudden death after COVID-19 vaccination in Thailand.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 vaccination reduces morbidity and mortality associated with coronavirus disease 2019 (COVID-19); unfortunately, it is associated with serious adverse events, including sudden unexplained death (SUD). OBJECTIVE: We aimed to study the genetic basis of SUD after COVID-19 vaccination in Thailand. METHODS: From April to December 2021, cases with natural but unexplained death within 7 days of COVID-19 vaccination were enrolled for whole exome sequencing. RESULTS: Thirteen were recruited, aged between 23 and 72 years; 10 (77%) were men, 12 were Thai; and 1 was Australian. Eight (61%) died after receiving the first dose of vaccine, and 7 (54%) died after receiving ChAdOx1 nCoV-19; however, there were no significant correlations between SUD and either the number or the type of vaccine. Fever was self-reported in 3 cases. Ten (77%) and 11 (85%) died within 24 hours and 3 days of vaccination, respectively. Whole exome sequencing analysis revealed that 5 cases harbored SCN5A variants that had previously been identified in patients with Brugada syndrome, giving an SCN5A variant frequency of 38% (5 of 13). This is a significantly higher rate than that observed in Thai SUD cases occurring 8-30 days after COVID-19 vaccination during the same period (10% [1 of 10]), in a Thai SUD cohort studied before the COVID-19 pandemic (12% [3 of 25]), and in our in-house exome database (12% [386 of 3231]). CONCLUSION: These findings suggest that SCN5A variants may be associated with SUD within 7 days of COVID-19 vaccination, regardless of vaccine type, number of vaccine dose, and presence of underlying diseases or postvaccine fever.

Phenotypic heterogeneity and genotypic spectrum of inborn errors of immunity identified through whole exome sequencing in a Thai patient cohort.

BACKGROUND: Inborn errors of immunity (IEI) comprise more than 400 rare diseases with potential life-threatening conditions. Clinical manifestations and genetic defects are heterogeneous and diverse among populations. Here, we aimed to characterize the clinical, immunologic, and genetic features of Thai pediatric patients with IEI. The use of whole-exome sequencing (WES) in diagnosis and clinical decision making was also assessed. METHODS: Thirty six unrelated patients with clinical and laboratory findings consistent with IEI were recruited from January 2010 to December 2020. WES was performed to identify the underlying genetic defects. RESULTS: The median age of disease onset was 4 months (range: 1 month to 13 years), and 24 were male (66.7%). Recurrent sinopulmonary tract infection was the most common clinical presentation followed by septicemia and severe pneumonia. Using WES, we successfully identified the underlying genetic defects in 18 patients (50%). Of the 20 variants identified, six have not been previously described (30%). According to the International Union of Immunological Societies (IUIS), 38.9% of these detected cases (7/18) were found to harbor variants associated with genes in combined immunodeficiencies with associated or syndromic features (Class II). CONCLUSION: The diagnostic yield of WES in this patient cohort was 50%. Six novel genetic variants in IEI genes were identified. The clinical usefulness of WES in IEI was demonstrated, emphasizing it as an effective diagnostic strategy in these genetically heterogeneous disorders.

Clinical and molecular characteristics of Thai patients with ELANE-related neutropaenia.

AIMS: Congenital neutropaenia is a rare inherited disorder that mainly affects neutrophils causing severe infection. Mutations in several genes have been implicated in the disease pathogenesis. The genetic defects may vary in different populations, influenced by ethnicity and geographical location. Here we describe the clinical and genotypic characteristics of seven unrelated Thai cases with congenital neutropaenia. METHODS: Seven unrelated patients with congenital neutropaenia were enrolled (5 female and 2 male) at King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Clinical and laboratory data were collected. Whole exome sequencing (WES) analysis was performed in all cases. RESULTS: WES successfully identified disease-causing mutations in the ELANE gene in all cases, including two novel ones: a heterozygous 12 base pair (bp) inframe insertion (c.289_300dupCAGGTGTTCGCC; p.Q97_A100dup) and a heterozygous 18 bp inframe deletion (c.698_715delCCCCGGTGGCACAGTTTG; p.A233_F238delAPVAQF). Five other previously described ELANE mutations (p.Arg103Pro, p.Gly214Arg, p.Trp241X, p.Ser126Leu and p.Leu47Arg) were also detected. CONCLUSIONS: All Thai patients with congenital neutropaenia in this study harboured causative mutations in the ELANE gene, suggesting it the most common associated with the disease. Two novel mutations were also identified, expanding the genotypic spectrum of ELANE.

Severe neonatal haemolytic anaemia caused by compound heterozygous KLF1 mutations: report of four families and literature review.

Mutations in the KLF1 gene, which encodes a transcription factor playing a role in erythropoiesis, have recently been demonstrated to be a rare cause of hereditary haemolytic anaemia. We described the genotypic and phenotypic spectra of four unrelated families with compound heterozygous class 2/class 3 KLF1 mutations. All patients had p.G176RfsX179 on one allele and either p.A298P, p.R301H or p.G335R on the other allele. All presented on the first day of life with severe haemolytic anaemia with abnormal red blood cell morphology, markedly increased nucleated red blood cells and hyperbilirubinaemia. Three patients later became transfusion-dependent. All parents with heterozygous KLF1 mutation without co-inherited thalassaemia had normal to borderline mean corpuscular volume (MCV) and normal to slightly elevated Hb F. Fifteen previously reported cases of biallelic KLF1 mutations were identified from a literature review. All except one presented with severe haemolytic anaemia in the neonatal period. Our finding substantiates that compound heterozygous KLF1 mutations are associated with severe neonatal haemolytic anaemia and expands the haematologic phenotypic spectrum. In carriers, the previously suggested findings of low MCV, high Hb A2 and high Hb F are inconsistent; thus this necessitates molecular studies for the identification of carriers.

Rapid exome sequencing as the first-tier investigation for diagnosis of acutely and severely ill children and adults in Thailand.

The use of rapid DNA sequencing technology in severely ill children in developed countries can accurately identify diagnoses and positively impact patient outcomes. This study sought to evaluate the outcome of Thai children and adults with unknown etiologies of critical illnesses with the deployment of rapid whole exome sequencing (rWES) in Thailand. We recruited 54 unrelated patients from 11 hospitals throughout Thailand. The median age was 3 months (range, 2 days-55 years) including 47 children and 7 adults with 52% males. The median time from obtaining blood samples to issuing the rWES report was 12 days (range, 5-27 days). A molecular diagnosis was established in 25 patients (46%), resulting in a change in clinical management for 24 patients (44%) resulting in improved clinical outcomes in 16 patients (30%). Four out of seven adult patients (57%) received the molecular diagnosis which led to a change in management. The 25 diagnoses comprised 23 different diseases. Of the 34 identified variants, 15 had never been previously reported. This study suggests that use of rWES as a first-tier investigation tool can provide tremendous benefits in critically ill patients with unknown etiology across age groups in Thailand.

Whole-Exome Sequencing Solved over 2-Decade Kidney Disease Enigma.

Chronic kidney disease of unknown etiology (CKDu) has been a problem in renal practice as indefinite diagnosis may lead to inappropriate management. Here, we report a 54-year-old father diagnosed with CKDu at 33 years old and his 8-year-old son with steroid-resistant nephrotic syndrome. Using whole-exome sequencing, both were found to be heterozygous for c.737G>A (p.Arg246Gln) in LMX1B. The diagnosis of LMX1B-associated nephropathy has led to changes in the treatment plan with appropriate genetic counseling. The previously reported cases with this particular mutation were also reviewed. Most children with LMX1B-associated nephropathy had nonnephrotic proteinuria with normal renal function. Interestingly, our pediatric case presented with steroid-resistant nephrotic syndrome at 8 years old and progressed to ESRD requiring peritoneal dialysis at the age of 15 years. Our report emphasized the need of genetic testing in CKDu for definite diagnosis leading to precise management.