Whole-exome analysis of 177 pediatric patients with undiagnosed diseases

Narita, Kentaro; Muramatsu, Hideki; Narumi, Shunji; Nakamura, Yuji; Suzuki, Kyogo; Hamada, Masanori; Yamaguchi, Naoya; Suzuki, Atsushi; Nishio, Yosuke; Shiraki, Anna; Yamamori, Ayako; Tsumura, Yusuke; Sawamura, Fumi; Kawaguchi, Masahiro; Wakamatsu, Mitsuru; Kataoka, Shinsuke; Kato, Kohji; Asada, H.; Muramatsu, Yoshiyuki; Kidokoro, Hiroyuki; Natsume, Jun; Mizuno, Seiji; Nakata, T.; Inagaki, Hidehito; Ishihara, Naoko; Yonekawa, Takahiro; Okumura, Akihisa; Ogi, Tomoo; Kojima, Seiji; Kaname, Tadashi; Hasegawa, Tomonobu; Saitoh, Shinji; Takahashi, Yoshiyuki

doi:10.1038/s41598-022-14161-6

Cited by 6 publications

(4 citation statements)

References 30 publications

(26 reference statements)

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“…WES can be applied in children with refractory epilepsy or epileptic encephalopathy ( 29 , 30 ). One study cohort consisted of 177 undiagnosed Japanese patients and yielded a 44% genetic diagnosis rate in children with complex diseases ( 31 ). However, for complex disorders, such as HS with other comorbidities, was not reported.…”

Section: Discussionmentioning

confidence: 99%

Syndromic and non-syndromic etiologies causing neonatal hypocalcemic seizures

Huang¹,

Chao²,

Lee³

2022

Front. Endocrinol.

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BackgroundThe diagnosis of neonatal hypocalcemic seizures (HS) in newborns is made based on clinical signs and serum calcium level. Their etiology is broad and diverse, and timely detection and initiation of treatment is essential.MethodsWe retrospectively reviewed 1029 patients admitted to the neonatal intensive care unit. Neonatal HS were diagnosed in 16 patients, and we compared etiologies and clinical outcomes, including clinical seizures and neurodevelopment at least over 1 year old.ResultsThe etiologies can be broadly categorized into 5 syndromic and 11 non-syndromic neonatal HS. Syndromic neonatal HS included 3 Digeorge syndrome, 1 Kleefstra syndrome and 1 Alström syndrome. Non-syndromic neonatal HS included 8 vitamin D deficiency, 1 hypoparathyroidism, and 2 hypoxic-ischemic encephalopathy. Patients with syndromic neonatal HS were found to have worse clinical outcomes than those with nonsyndromic HS. In eight patients with vitamin D deficiency, neurodevelopment was normal. Five of five patients (100%) with syndromic HS used two or more antiseizure drugs. However, among patients with non-syndromic neonatal HS, only one of 11 (9.1%) used more than one drug (p = 0.001).ConclusionThis finding highlighted that syndromic hypocalcemic seizures in newborns have worse neurodevelopmental outcomes and are more often difficult to manage, and would benefit from a genetic diagnostic approach.

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Section: Discussionmentioning

confidence: 99%

Syndromic and non-syndromic etiologies causing neonatal hypocalcemic seizures

Huang¹,

Chao²,

Lee³

2022

Front. Endocrinol.

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“…According to the recommendations, the genetic background of AS can be investigated using methods that are endorsed by geneticists and reimbursed, such as FISH, aCGH microarray, or molecular analysis of the UBE3A gene sequence. WES testing should be reserved for rare cases with diagnostic di culties that cannot be detected by other molecular methods 17,18 . The WES test cannot unambiguously assess the most common cause of AS, which is abnormalities in the methylation pattern of the critical 15q11-q13 region associated with AS.…”

Section: The Wes Studymentioning

confidence: 99%

Angelman syndrome in Poland: current diagnosis and therapy status – the caregiver perspective – a questionnaire study

Agata,

Katarzyna,

Łukasz

et al. 2024

Preprint

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Background Angelman syndrome (AS) is a rare neurodevelopmental disease caused by imprinting disorders that impede the production of the ubiquitin E3A ligase protein (UBE3A). AS affects multiple systems, with the main symptoms including epilepsy, psychomotor disorders and speech development disorders. To date, no study has been conducted in the Polish population to verify the condition's diagnosis and treatment process. Results Seventy patients with the median age of 60 months were included into the analysis. 80% of patients were diagnosed with deletion, 19.9% with a mutation of UBE3A gene, 4.3% with paternal uniparental disomy (UPD) and 2.8% with an imprinting defect. The mean age of first symptoms was 5 months, while the mean age of diagnosis was 29 months (earliest in deletion group at 23 months), and the median duration of diagnosis process was 7 months. The average time to a clinical geneticist appointment was 3 months. 37.9% of the patients initially received a different diagnosis. Epileptic seizures were present in 88.6% of the individuals. 98.6% of the studied group were under care of a pediatric neurologist, 47.1% of a gastroenterologist. A ketogenic diet was used in 7.1% of patients. Caregivers identified finding a specialist suitable for AS patients and access to genetic testing as the biggest problems. Conclusions The care of patients with AS in Poland is carried out according to the European and world standards, however there is an impeded access to clinical geneticist, and the knowledge about rare diseases among primary healthcare physicians could be improved. Moreover, access to AS care specialists and coordination of care is limited. There is a need for creation a specialized centers and databases for AS patients.

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“…Feliciano et al [15] reported that the diagnostic yield of ES for detecting SNVs/indels and CNVs in ASD was 10.4% in 457 families. Although the diagnostic rate of ES depends on the cohort and target disease that is being assessed, its rate in ASD is lower than that in other genetic conditions, which have usually been reported as 25%-44% [16,17]. However, many aberrant disease-causing genes have been identified over the years, and 10-15% of unresolved cases may obtain a molecular diagnosis by reanalysis (reviewed by Lee and Nelson [18]).…”

Section: Introductionmentioning

confidence: 99%

Molecular diagnosis of 405 individuals with autism spectrum disorder

et al. 2023

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Autism spectrum disorder (ASD) is caused by combined genetic and environmental factors. Genetic heritability in ASD is estimated as 60-90%, and genetic investigations have revealed many monogenic factors. We analyzed 405 patients with ASD using familybased exome sequencing to detect disease-causing single-nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variations (CNVs) for molecular diagnoses. All candidate variants were validated by Sanger sequencing or quantitative polymerase chain reaction and were evaluated using the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for molecular diagnosis. We identified 55 disease-causing SNVs/indels in 53 affected individuals and 13 disease-causing CNVs in 13 affected individuals, achieving a molecular diagnosis in 66 of 405 affected individuals (16.3%). Among the 55 disease-causing SNVs/indels, 51 occurred de novo, 2 were compound heterozygous (in one patient), and 2 were X-linked hemizygous variants inherited from unaffected mothers. The molecular diagnosis rate in females was significantly higher than that in males. We analyzed affected sibling cases of 24 quads and 2 quintets, but only one pair of siblings shared an identical pathogenic variant. Notably, there was a higher molecular diagnostic rate in simplex cases than in multiplex families. Our simulation indicated that the diagnostic yield is increasing by 0.63% (range 0-2.5%) per year. Based on our simple simulation, diagnostic yield is improving over time. Thus, periodical reevaluation of ES data should be strongly encouraged in undiagnosed ASD patients.

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Whole-exome analysis of 177 pediatric patients with undiagnosed diseases

Cited by 6 publications

References 30 publications

Syndromic and non-syndromic etiologies causing neonatal hypocalcemic seizures

Syndromic and non-syndromic etiologies causing neonatal hypocalcemic seizures

Angelman syndrome in Poland: current diagnosis and therapy status – the caregiver perspective – a questionnaire study

Molecular diagnosis of 405 individuals with autism spectrum disorder

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