Biallelic loss of <i>OTUD7A</i> causes severe muscular hypotonia, intellectual disability, and seizures

Suzuki, Hisato; Inaba, Masafumi; Yamada, Mamiko; Uehara, Tomoko; Tamura, Toshiki; Mizuno, Seiji; Kosaki, Kenjiro; Doi, Motomichi

doi:10.1002/ajmg.a.62054

Cited by 17 publications

(11 citation statements)

References 17 publications

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“…This change may remove the C-terminal Zinc finger A20-type domain and abolish the normal function of the protein. Our finding in Subject #4, together with recent case reports of patients with a homozygous missense OTUD7A variant alleles (Garret et al 2020), or compound heterozygous 15q13.3 deletion in trans with a frameshift OTUD7A variant (Suzuki et al 2020), supports our contention and corroborates that OTUD7A may be the critical ‘driver gene’ in the 15q13.3 deletion syndrome. OTUD7A may be sensitive to gene dosage effect, and contribute to disease etiology at least in part through a biallelic AR disease trait mechanism.…”

Section: Resultssupporting

confidence: 90%

Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits

Yuan

Schulze

Batzir

et al. 2021

Preprint

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In medical genetics, discovery and characterization of new "disease genes" and alleles depend on patient ascertainment strategies to enrich previously uncharacterized alleles. Here, we present a novel strategy of new allele and gene discovery for recessive/biallelic disease traits. In this approach, patients with large recurrent genomic deletions mediated by nonallelic homologous recombination (NAHR) are sequenced, and new discoveries are revealed in the hemizygous chromosomal regions in trans to the large deletion, essentially enabling haploid genomic segment genetics. We demonstrate through computational analyses that a collection of 30 large recurrent genomic deletions scattered in the human genome contribute to more than 10% of individual disease load for 2.13% of all known "recessive disease genes". We performed meta-analyses for all literature reported patients affected with the 13 genes whose carrier burden are predicted to be almost exclusively from large recurrent genomic deletions. The results suggest that current sequencing efforts for personal genomes with large recurrent deletions is under-appreciated. By retrospective analyses of previously undiagnostic exome sequencing (ES) data on 69 subjects harboring 26 types of recurrent deletions, probable diagnostic variants were uncovered in genes including COX10, ERCC6, PRRT2 and OTUD7A, demonstrating new disease allele/gene/mechanism characterization. Findings from this study support the contention that more whole genome sequencing (WGS) may further resolve molecular diagnoses and provide evidence for multi-locus pathogenic variation (MPV). Such analyses benefit all stakeholders in both research development and patient clinical care.

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Section: Resultssupporting

confidence: 90%

Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits

Yuan

Schulze

Batzir

et al. 2021

Preprint

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“…His parents and a younger brother who manifested learning disability were heterozygous carriers of the missense mutation (Garret et al, 2020). Suzuki and colleagues also reported the biallelic loss of function of OTUD7A in a male patient with hypotonia, intellectual disability, and seizures (Suzuki et al, 2021). These findings suggest the OTUD7A plays a critical role in brain development, and haploinsufficiency of the OTUD7A may contribute to the pathogenesis of our patient.…”

Section: Discussionsupporting

confidence: 56%

Chromosomal Microarray Analysis as First-Tier Genetic Test for Schizophrenia

Chen

Cheng

et al. 2021

Front. Genet.

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Schizophrenia is a chronic, devastating mental disorder with complex genetic components. Given the advancements in the molecular genetic research of schizophrenia in recent years, there is still a lack of genetic tests that can be used in clinical settings. Chromosomal microarray analysis (CMA) has been used as first-tier genetic testing for congenital abnormalities, developmental delay, and autism spectrum disorders. This study attempted to gain some experience in applying chromosomal microarray analysis as a first-tier genetic test for patients with schizophrenia. We consecutively enrolled patients with schizophrenia spectrum disorder from a clinical setting and conducted genome-wide copy number variation (CNV) analysis using a chromosomal microarray platform. We followed the 2020 “Technical Standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)” to interpret the clinical significance of CNVs detected from patients. We recruited a total of 60 patients (36 females and 24 males) into this study. We detected three pathogenic CNVs and one likely pathogenic CNV in four patients, respectively. The detection rate was 6.7% (4/60, 95% CI: 0.004–0.13), comparable with previous studies in the literature. Also, we detected thirteen CNVs classified as uncertain clinical significance in nine patients. Detecting these CNVs can help establish the molecular genetic diagnosis of schizophrenia patients and provide helpful information for genetic counseling and clinical management. Also, it can increase our understanding of the pathogenesis of schizophrenia. Hence, we suggest CMA is a valuable genetic tool and considered first-tier genetic testing for schizophrenia spectrum disorders in clinical settings.

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“…The general applicability of the proposed method, which was successful in the two examples of OTUD7A (Suzuki et al, 2021) and SMPD4, needs further verification. It is very likely that smaller CNVs have been missed by EXCAVATOR2 due to detection limit of CNVs innate to algorithm based on copy number estimation from read depth.…”

Section: Discussionmentioning

confidence: 93%

A patient with compound heterozygosity of SMPD4: Another example of utility of exome‐based copy number analysis in autosomal recessive disorders

Yamada

Suzuki

Taguchi

et al. 2021

American J of Med Genetics Pt A

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For the efficient diagnosis of rare and undiagnosed diseases, the parallel detection of copy number variants (CNVs) and single nucleotide variants using exome analysis is required. Recently, our group reported the usefulness of a program called EXCAVATOR2, which screens for CNVs from aligned exome data in bam format. This method is expected to contribute to the identification of structural variants and to improve the diagnosis rate, especially for the diagnosis of autosomal recessive disease, when a conventional exome analysis identifies a pathogenic variant in one allele but not the other. Here we report a 2‐year‐old Japanese boy with an undiagnosed disease. He had severe neonatal asphyxia, severe intellectual disability, intractable seizures, cerebellar and brainstem hypoplasia and dysmorphic features including a prominent supraorbital ridge, thin upper lip, and prominent antihelix. An exome analysis reinforced with a copy number analysis using the EXCAVATOR2 method revealed that the patient had a hemizygous variant in chr2(GRCh37):g.130925108G>A, NM_017951.4 c.832C>T, p.(Arg278*) in SMPD4 that was derived from his father and a deletion of SMPD4 derived from his mother. The presence of the deletion spanning SMPD4 was confirmed by short‐read and long‐read whole‐genome sequencing. The successful diagnosis of this reported patient demonstrates the diagnostic utility of EXCAVATOR2 and overcomes the weakness of exome analysis for the detection of autosomal recessive diseases in nonconsanguineous families, significantly impacting genetic counseling for family planning.

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Biallelic loss of OTUD7A causes severe muscular hypotonia, intellectual disability, and seizures

Cited by 17 publications

References 17 publications

Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits

Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits

Chromosomal Microarray Analysis as First-Tier Genetic Test for Schizophrenia

A patient with compound heterozygosity of SMPD4: Another example of utility of exome‐based copy number analysis in autosomal recessive disorders

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