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Journal of Human Genetics

Zhongmin Xia, Yulin Zhou, Dongmei Fu, Zengge Wang, Yunsheng Ge, Jun Ren, Qiwei Guo
Carrier screening of spinal muscular atrophy (SMA) can provide reproductive options for carriers and prevent the birth defects. Here, we developed a simple screening test based on melting analysis. The test comprises a duplex PCR with two primer pairs and three probes to simultaneous amplify SMN1, SMN2, and CFTR. By analyzing the melting profiles, we were able to determine the SMN1/SMN2 ratio and SMN1 + SMN2 copy number to subsequently determine the copy number of SMN1. Samples with one copy of SMN1 were considered as "high risk for carrier," while samples with ≥2 copies of SMN1 were considered as "low risk for carrier...
February 15, 2019: Journal of Human Genetics
Hiromi Aoi, Ming Lei, Takeshi Mizuguchi, Nobuko Nishioka, Tomohide Goto, Sahoko Miyama, Toshifumi Suzuki, Kazuhiro Iwama, Yuri Uchiyama, Satomi Mitsuhashi, Atsuo Itakura, Satoru Takeda, Naomichi Matsumoto
We herein report two individuals with novel nonsense mutations in STAG2 on Xq25, encoding stromal antigen 2, a component of the cohesion complex. A male fetus (Case 1) clinically presented with holoprosencephaly, cleft palate and lip, blepharophimosis, nasal bone absence, and hypolastic left heart by ultrasonography at 15 gestational weeks. Another female patient (Case 2) showed a distinct phenotype with white matter hypoplasia, cleft palate, developmental delay (DD), and intellectual disability (ID) at 7 years...
February 14, 2019: Journal of Human Genetics
Ling Wu, Hua Chen, Da Li, Di Song, Biaobang Chen, Zheng Yan, Qifeng Lyu, Lei Wang, Yanping Kuang, Bin Li, Qing Sang
Oocyte maturation arrest results in primary female infertility, but the genetic etiology of this phenotype remains largely unknown. Previously, we and other groups have reported that biallelic mutations in PATL2 are mainly responsible for human oocyte germinal vesicle-stage arrest and that the specific phenotype varies for different mutations. Here, we identified four novel missense mutations (p.V260M, p.Q300*, p.T425P, and p.D293Y), a novel frameshift mutation (p.N239Tfs*9), and a reported splicing mutation (p...
February 14, 2019: Journal of Human Genetics
Jacob D Spector, Arun P Wiita
Standard clinical interpretation of DNA copy number variants (CNVs) identified by cytogenomic microarray involves examining protein-coding genes within the region and comparison to other CNVs. Emerging basic research suggests that CNVs can also exert a pathogenic effect through disruption of DNA structural elements such as topologically associated domains (TADs). To begin to integrate these discoveries with current practice, we developed ClinTAD, a free browser-based tool to assist with interpretation of CNVs in the context of TADs ( www...
February 14, 2019: Journal of Human Genetics
Takeshi Mizuguchi, Takeshi Suzuki, Chihiro Abe, Ayako Umemura, Katsushi Tokunaga, Yosuke Kawai, Minoru Nakamura, Masao Nagasaki, Kengo Kinoshita, Yasunobu Okamura, Satoko Miyatake, Noriko Miyake, Naomichi Matsumoto
We report a family with progressive myoclonic epilepsy who underwent whole-exome sequencing but was negative for pathogenic variants. Similar clinical courses of a devastating neurodegenerative phenotype of two affected siblings were highly suggestive of a genetic etiology, which indicates that the survey of genetic variation by whole-exome sequencing was not comprehensive. To investigate the presence of a variant that remained unrecognized by standard genetic testing, PacBio long-read sequencing was performed...
February 13, 2019: Journal of Human Genetics
Meng-Jiao Zhu, Xiao-Yun Ma, Pei-Cheng Ding, Han-Fei Tang, Rui Peng, Lei Lu, Pei-Qiang Li, Bin Qiao, Xue-Yan Yang, Yu-Fang Zheng, Hong-Yan Wang, Yun-Qian Gao, Feng-Shan Chen
Congenital heart defects (CHDs), the most common congenital human birth anomalies, involves complex genetic factors. Wnt/β-catenin pathway is critical for cardiogenesis and proved to be associated with numerous congenital heart abnormities. AXIN2 has a unique role in Wnt/β-catenin pathway, as it is not only an important inhibitor but also a direct target of Wnt/β-catenin pathway. However, whether AXIN2 is associated with human CHDs has not been reported. In our present study, we found a differential expression of Axin2 mRNA during the development of mouse heart, indicating its importance in mouse cardiac development...
February 13, 2019: Journal of Human Genetics
Akiko Nagai, Izen Ri, Kaori Muto
The version of this article originally published was not open access. This article should have been open access. The error has been fixed, and the article is now open access.
February 12, 2019: Journal of Human Genetics
Lidia Ruiz-Llorente, Jamie McDonald, Whitney Wooderchak-Donahue, Eric Briggs, Mark Chesnutt, Pinar Bayrak-Toydemir, Carmelo Bernabeu
Hereditary hemorrhagic telangiectasia (HHT) is a vascular disease characterized by nose and gastrointestinal bleeding, telangiectases in skin and mucosa, and arteriovenous malformations in major internal organs. Most patients carry a mutation in the coding region of the endoglin (ENG) or activin A receptor type II-1 (ACVRL1) gene. Nonetheless, in around 15% of patients, sequencing analysis and duplication/deletion tests fail to pinpoint mutations in the coding regions of these genes. In these cases, it has been shown that sequencing of the 5'-untranslated region (5'UTR) of ENG may be useful to identify novel mutations in the ENG non-coding region...
February 6, 2019: Journal of Human Genetics
Piranit Nik Kantaputra, Yuddhasert Sirirungruangsarn, Pannee Visrutaratna, Sasitorn Petcharunpaisan, Bruce M Carlson, Worrachet Intachai, Jutamas Sudasna, Jatupol Kampuansai, Prapai Dejkhamron
A rare form of osteogenesis imperfecta (OI) caused by Wingless-type MMTV integration site family 1 (WNT1) mutations combines central nervous system (CNS) anomalies with the characteristic increased susceptibility to fractures. We report an additional case where arachnoid cysts extend the phenotype, and that also confirms the association of intellectual disabilities with asymmetric cerebellar hypoplasia here. Interestingly, if the cerebellum is normal in this disorder, intelligence is as well, analogous to an association with similar delays in a subset of patients with sporadic unilateral cerebellar hypoplasia...
January 28, 2019: Journal of Human Genetics
Sumito Dateki, Satoshi Watanabe, Hiroyuki Mishima, Toshihiko Shirakawa, Minoru Morikawa, Eiichi Kinoshita, Koh-Ichiro Yoshiura, Hiroyuki Moriuchi
The genetic causes of combined pituitary hormone deficiency remain elusive in most patients. Recently, incompletely penetrant heterozygous mutations in ROBO1 have been described in patients with pituitary stalk interruption syndrome. Herein, we identified a novel homozygous slice site mutation in ROBO1 (c.1342+1G>A) using a trio whole-exome sequencing strategy in a 5-year-old Japanese boy who had combined pituitary hormone deficiency, psychomotor developmental delay, severe intellectual disability, sensorineural hearing loss, strabismus, and characteristic facial features, including a broad forehead, micrognathia, and arched eyebrows...
January 28, 2019: Journal of Human Genetics
Dhanya Lakshmi Narayanan, Divya Matta, Neerja Gupta, Madhulika Kabra, Prajnya Ranganath, Shagun Aggarwal, Shubha R Phadke, Chaitanya Datar, Kalpana Gowrishankar, Mahesh Kamate, Jamal Mohammed Nurul Jain, Ashwin Dalal
Metachromatic leukodystrophy due to Arylsulfatase A enzyme deficiency is an autosomal recessive disorder caused by biallelic variations in ARSA gene. Till date 186 variations have been reported in ARSA gene worldwide, but the variation spectrum in India is not known. The aim of this study was to identify the variation profile in Indian patients presenting with features of Arylsulfatase A deficient metachromatic leukodystrophy. We sequenced the ARSA gene in 51 unrelated families and identified 36 variants out of which 16 were novel...
January 23, 2019: Journal of Human Genetics
Heba Yasin, William T Gibson, Sylvie Langlois, Robert M Stowe, Erica S Tsang, Leora Lee, Jenny Poon, Grant Tran, Christine Tyson, Chi Kin Wong, Marco A Marra, Jan M Friedman, Farah R Zahir
A decade ago, we described novel de novo submicroscopic deletions of chromosome 14q11.2 in three children with developmental delay, cognitive impairment, and similar dysmorphic features, including widely-spaced eyes, short nose with flat nasal bridge, long philtrum, prominent Cupid's bow of the upper lip, full lower lip, and auricular anomalies. We suggested that this constituted a new multiple congenital anomaly-intellectual disability syndrome due to defects in CHD8 and/or SUPT16H. The three patients in our original cohort were between 2 years and 3 years of age at the time...
January 22, 2019: Journal of Human Genetics
Mei Lu, Yulin Zhou, Zengge Wang, Zhongmin Xia, Jun Ren, Qiwei Guo
COQ4 mutations have recently been shown to cause a broad spectrum of mitochondrial disorders in association with CoQ10 deficiency. Herein, we report the clinical phenotype, in silico and biochemical analyses, and intervention for a novel c.370 G > A (p.G124S) COQ4 mutation in a Chinese family. This mutation is exclusively present in the East Asian population (allele frequency of ~0.001). The homozygous mutation caused CoQ10 deficiency-associated Leigh syndrome with an onset at 1-2 months of age, presenting as respiratory distress, lactic acidosis, dystonia, seizures, failure to thrive, and detectable lesions in the midbrain and basal ganglia...
January 18, 2019: Journal of Human Genetics
Mitsuko Nakashima, Jun Tohyama, Eiji Nakagawa, Yoshihiro Watanabe, Ch'ng Gaik Siew, Chieng Siik Kwong, Kaori Yamoto, Takuya Hiraide, Tokiko Fukuda, Tadashi Kaname, Kazuhiko Nakabayashi, Kenichiro Hata, Tsutomu Ogata, Hirotomo Saitsu, Naomichi Matsumoto
Casein kinase 2 (CK2) is a serine threonine kinase ubiquitously expressed in eukaryotic cells and involved in various cellular processes. In recent studies, de novo variants in CSNK2A1 and CSNK2B, which encode the subunits of CK2, have been identified in individuals with intellectual disability syndrome. In this study, we describe four patients with neurodevelopmental disorders possessing de novo variants in CSNK2A1 or CSNK2B. Using whole-exome sequencing, we detected two de novo variants in CSNK2A1 in two unrelated Japanese patients, a novel variant c...
January 17, 2019: Journal of Human Genetics
Ana Krivokuca, Ivana Boljevic, Stevo Jovandic, Zvonko Magic, Aljosa Mandic, Zorica Tomasevic, Mirjana Brankovic-Magic
Clinical criteria for genetic testing of genes other than BRCA1/2 in epithelial ovarian cancer (EOC) still do not exist. We assessed the frequency and predictors of deleterious mutations in 19 cancer predisposition genes in high-grade serous ovarian cancer (HGSOC) in Serbia. Next-generation sequencing was used to identify germline mutations in the whole coding regions of a gene panel. Patients' characteristics and sequencing data were summarized with descriptive statistics and compared using chi-square test...
January 16, 2019: Journal of Human Genetics
Yi Liu, Lulu Kang, Dongxiao Li, Ying Jin, Jinqing Song, Haixia Li, Junjuan Wang, Yanling Yang
Cobalamin G (cblG) and cobalamin J (cblJ) defects are rare disorders of cbl metabolism caused by MTR and ABCD4 mutations, respectively. Patients with atypical biochemical features can be missed by current newborn screening using tandem mass spectrometry (MS/MS), in which total homocysteine (tHCY) in dried blood spots (DBS) is not a primary biomarker. Two Chinese patients suspected of cbl defect but missed by newborn screening were studied. Using comprehensive metabolic analyses including MS/MS assay for tHCY in DBS, slightly low methionine in Patient 1, methymalonic aciduria in Patient 2, and homocysteinemia in both patients were detected, and DBS tHCY of two patients were obviously elevated (59...
January 16, 2019: Journal of Human Genetics
Naoyuki Kamatani, Akifumi Kushiyama, Licht Toyo-Oka, Teruhiko Toyo-Oka
Since mitochondria are energy-generating micro-organisms, most of the disorders in patients with mitochondrial diseases (mt-disease) are considered secondary to defects in ATP synthesis, although some other factors such as reactive oxygen species may be involved. A simultaneous oral administration of febuxostat and inosine was reported to elevate both hypoxanthine and ATP levels in peripheral blood. Based on those results, we attempted co-administration of febuxostat and inosine in two patients with mitochondrial disease: one patient with mitochondrial cardiomyopathy and the other patient with mitochondrial diabetes...
January 10, 2019: Journal of Human Genetics
Akiko Nagai, Izen Ri, Kaori Muto
Genomic tumor profiling tests (GTPTs) to find molecular targeted drugs for patients with advanced cancer are being introduced into clinical settings, which may result in secondary germline findings. Although small-scale qualitative studies have revealed patients' attitudes toward GTPTs and preferences on receiving germline findings, no large-scale quantitative research exists that includes family members. We conducted anonymous surveys with 757 cancer patients (CPs), 763 family members (FMs), and 3697 general adults (GAs) in Japan...
January 10, 2019: Journal of Human Genetics
Takeshi Mizuguchi, Mitsuko Nakashima, Lip H Moey, Gaik S Ch'ng, Teik-Beng Khoo, Satomi Mitsuhashi, Satoko Miyatake, Atsushi Takata, Noriko Miyake, Hirotomo Saitsu, Naomichi Matsumoto
We report the second case of early infantile epileptic encephalopathy (EIEE) arising from a homozygous truncating variant of NECAP1. The boy developed infantile-onset tonic-clonic and tonic seizures, then spasms in clusters. His electroencephalogram (EEG) showed a burst suppression pattern, leading to the diagnosis of Ohtahara syndrome. Whole-exome sequencing revealed the canonical splice-site variant (c.301 + 1 G > A) in NECAP1. In rodents, Necap1 protein is enriched in neuronal clathrin-coated vesicles and modulates synaptic vesicle recycling...
January 9, 2019: Journal of Human Genetics
Jéssika V Okumura, Danilo G H Silva, Lidiane S Torres, Edis Belini-Junior, Larissa P R Venancio, Gisele C S Carrocini, Patrícia P Nascimento, Clarisse L C Lobo, Claudia R Bonini-Domingos
β-S globin haplotype (βS haplotype) characterization in sickle cell anemia (SCA) patients is important because it assists individualized treatment. However, the patient with atypical haplotypes do not present detailed studies such as clinical and laboratory data. To understand the phenotypic expression of atypical haplotype patients in relation to typical haplotype ones, it may be necessary to assess the main clinical and laboratorial parameters and investigate transcription factors, as possible genetic modulators that can contribute to the improvement of the SCA patients' clinical condition...
January 9, 2019: Journal of Human Genetics
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