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A novel ITPA variant causes epileptic encephalopathy with multiple-organ dysfunction

Sakamoto M, Kouhei D, Haniffa M, Silva S, Troncoso M, Santander P, et al.

J Hum Genet, 2020 Sep;65(9):751-757.
PMID: 32405030 DOI: 10.1038/s10038-020-0765-3

Inborn errors of metabolism can cause epileptic encephalopathies. Biallelic loss-of-function variants in the ITPA gene, encoding inosine triphosphate pyrophosphatase (ITPase), have been reported in epileptic encephalopathies with lack of myelination of the posterior limb of the internal capsule, brainstem tracts, and tracts to the primary visual and motor cortices (MIM:616647). ITPase plays an important role in purine metabolism. In this study, we identified two novel homozygous ITPA variants, c.264-1 G > A and c.489-1 G > A, in two unrelated consanguineous families. The probands had epilepsy, microcephaly with characteristic magnetic resonance imaging findings (T2 hyperintensity signals in the pyramidal tracts of the internal capsule, delayed myelination, and thin corpus callosum), hypotonia, and developmental delay; both died in early infancy. Our report expands the knowledge of clinical consequences of biallelic ITPA variants.
Biallelic null variants in ZNF142 cause global developmental delay with familial epilepsy and dysmorphic features

Kameyama S, Mizuguchi T, Fukuda H, Moey LH, Keng WT, Okamoto N, et al.

J Hum Genet, 2021 Sep 17.
PMID: 34531528 DOI: 10.1038/s10038-021-00978-y

Biallelic variants in ZNF142 at 2q35, which encodes zinc-finger protein 142, cause neurodevelopmental disorder with seizures or dystonia. We identified compound heterozygous null variants in ZNF142, NM_001105537.4:c.[1252C>T];[1274-2A>G],p.[Arg418*];[Glu426*], in Malaysian siblings suffering from global developmental delay with epilepsy and dysmorphism. cDNA analysis showed the marked reduction of ZNF142 transcript level through nonsense-mediated mRNA decay by these novel biallelic variants. The affected siblings present with global developmental delay and epilepsy in common, which were previously described, as well as dysmorphism, which was not recognized. It is important to collect patients with ZNF142 abnormality to define its phenotypic spectrum.
Fulltext Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy

Miyake N, Fukai R, Ohba C, Chihara T, Miura M, Shimizu H, et al.

Am J Hum Genet, 2016 Oct 06;99(4):950-961.
PMID: 27666374 DOI: 10.1016/j.ajhg.2016.08.005

We describe four families with affected siblings showing unique clinical features: early-onset (before 1 year of age) progressive diffuse brain atrophy with regression, postnatal microcephaly, postnatal growth retardation, muscle weakness/atrophy, and respiratory failure. By whole-exome sequencing, we identified biallelic TBCD mutations in eight affected individuals from the four families. TBCD encodes TBCD (tubulin folding co-factor D), which is one of five tubulin-specific chaperones playing a pivotal role in microtubule assembly in all cells. A total of seven mutations were found: five missense mutations, one nonsense, and one splice site mutation resulting in a frameshift. In vitro cell experiments revealed the impaired binding between most mutant TBCD proteins and ARL2, TBCE, and β-tubulin. The in vivo experiments using olfactory projection neurons in Drosophila melanogaster indicated that the TBCD mutations caused loss of function. The wide range of clinical severity seen in this neurodegenerative encephalopathy may result from the residual function of mutant TBCD proteins. Furthermore, the autopsied brain from one deceased individual showed characteristic neurodegenerative findings: cactus and somatic sprout formations in the residual Purkinje cells in the cerebellum, which are also seen in some diseases associated with mitochondrial impairment. Defects of microtubule formation caused by TBCD mutations may underlie the pathomechanism of this neurodegenerative encephalopathy.
Molecular diagnosis of 405 individuals with autism spectrum disorder

Miyake N, Tsurusaki Y, Fukai R, Kushima I, Okamoto N, Ohashi K, et al.

Eur J Hum Genet, 2023 Mar 27.
PMID: 36973392 DOI: 10.1038/s41431-023-01335-7

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 family-based 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.
Efficient detection of copy-number variations using exome data: Batch- and sex-based analyses

Uchiyama Y, Yamaguchi D, Iwama K, Miyatake S, Hamanaka K, Tsuchida N, et al.

Hum Mutat, 2021 01;42(1):50-65.
PMID: 33131168 DOI: 10.1002/humu.24129

Many algorithms to detect copy number variations (CNVs) using exome sequencing (ES) data have been reported and evaluated on their sensitivity and specificity, reproducibility, and precision. However, operational optimization of such algorithms for a better performance has not been fully addressed. ES of 1199 samples including 763 patients with different disease profiles was performed. ES data were analyzed to detect CNVs by both the eXome Hidden Markov Model (XHMM) and modified Nord's method. To efficiently detect rare CNVs, we aimed to decrease sequencing biases by analyzing, at the same time, the data of all unrelated samples sequenced in the same flow cell as a batch, and to eliminate sex effects of X-linked CNVs by analyzing female and male sequences separately. We also applied several filtering steps for more efficient CNV selection. The average number of CNVs detected in one sample was <5. This optimization together with targeted CNV analysis by Nord's method identified pathogenic/likely pathogenic CNVs in 34 patients (4.5%, 34/763). In particular, among 142 patients with epilepsy, the current protocol detected clinically relevant CNVs in 19 (13.4%) patients, whereas the previous protocol identified them in only 14 (9.9%) patients. Thus, this batch-based XHMM analysis efficiently selected rare pathogenic CNVs in genetic diseases.
Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy

Sakamoto M, Iwama K, Sasaki M, Ishiyama A, Komaki H, Saito T, et al.

Genet Med, 2022 Dec;24(12):2453-2463.
PMID: 36305856 DOI: 10.1016/j.gim.2022.08.007

PURPOSE: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects.
METHODS: Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated.
RESULTS: Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments.
CONCLUSION: A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.
Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients

Sekiguchi F, Tsurusaki Y, Okamoto N, Teik KW, Mizuno S, Suzumura H, et al.

J Hum Genet, 2019 Dec;64(12):1173-1186.
PMID: 31530938 DOI: 10.1038/s10038-019-0667-4

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.