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Human Genome Variation

Miki Watanabe, Ryuji Nakagawa, Tomohiro Kohmoto, Takuya Naruto, Ken-Ichi Suga, Aya Goji, Hideaki Horikawa, Kiyoshi Masuda, Shoji Kagami, Issei Imoto
Lowe syndrome (LS) is an X-linked disorder affecting the eyes, nervous system and kidneys, typically caused by missense or nonsense/frameshift OCRL mutations. We report a 6-month-old male clinically suspected to have LS, but without the Fanconi-type renal dysfunction. Using a targeted-exome sequencing-first approach, LS was diagnosed by the identification of a deletion involving 1.7 Mb at Xq25-q26.1, encompassing the entire OCRL gene and neighboring loci.
2016: Human Genome Variation
Vida Čulić, Noriko Miyake, Sunčana Janković, Davor Petrović, Marko Šimunović, Tomislav Đapić, Masaaki Shiina, Kazuhiro Ogata, Naomichi Matsumoto
Distal arthrogryposis (DA) is a clinically and genetically heterogeneous disorder with multiple joint contractures. We describe a female DA patient with hand and foot deformities, and right-sided torticollis. Using exome sequencing, we identified a novel TNNI2 mutation (c.485>A, p.Arg162Lys) in the patient and her father. The father has no typical DA but hip dysplasia. This may explain the clinical features of DA2B in this family, but with variable clinical expression.
2016: Human Genome Variation
Masaki Takagi, Tatsuya Miyoshi, Yuka Nagashima, Nao Shibata, Hiroko Yagi, Ryuji Fukuzawa, Tomonobu Hasegawa
Heterozygous kinase domain mutations or homozygous extracellular domain mutations in FGFR1 have been reported to cause Hartsfield syndrome (HS), which is characterized by the triad of holoprosencephaly, ectrodactyly and cleft lip/palate. To date, more than 200 mutations in FGFR1 have been described; however, only 10 HS-associated mutations have been reported thus far. We describe a case of typical HS with hypogonadotropic hypogonadism (HH) harboring a novel heterozygous mutation, p.His253Pro, in the extracellular domain of FGFR1...
2016: Human Genome Variation
Keiko Shimojima, Yumiko Ondo, Eriko Nishi, Seiji Mizuno, Miharu Ito, Aya Ioi, Mariko Shimizu, Maho Sato, Masami Inoue, Nobuhiko Okamoto, Toshiyuki Yamamoto
Simpson-Golabi-Behmel syndrome is a congenital malformation syndrome associated with mutations in GPC3, which is located in the Xq26 region. Three new loss-of-function mutations and a global X-chromosome rearrangement involving GPC3 were identified. A female sibling of the patient, who presented with a cleft palate and hepatoblastoma, carries the same chromosomal rearrangement and a paradoxical pattern of X-chromosome inactivation. These findings support variable GPC3 alterations, with a possible mechanism in female patients...
2016: Human Genome Variation
Kengo Hirota, Hiroyuki Akagawa, Asami Kikuchi, Hideki Oka, Akihiko Hino, Tetsuryu Mitsuyama, Toshiyuki Sasaki, Hideaki Onda, Takakazu Kawamata, Hidetoshi Kasuya
Cerebral cavernous malformation is a neurovascular abnormality that can cause seizures, focal neurological deficits and intracerebral hemorrhage. Familial forms of this condition are characterized by de novo formation of multiple lesions and are autosomal-dominantly inherited via CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10 mutations. We identified three truncating mutations in KRIT1 from three Japanese families with CCMs: a novel frameshift mutation, a known frameshift mutation and a known splice-site mutation that had not been previously analyzed for aberrant splicing...
2016: Human Genome Variation
Catherine Breen, Jean Mercer, Simon A Jones, Amir Jahic, Lesley Heptinstall, Karen Tylee, William G Newman, Christian Beetz
Mucopolysaccharidosis I (MPS I) is a rare autosomal recessive multisystem lysosomal storage disorder. It is caused by biallelic loss-of-function variants in IDUA, encoding alpha-l iduronidase. Here, we describe an individual affected by MPS I due to a paternally inherited deletion of IDUA exons 1 and 2, c.(?_-88)_(299+1_300-1)del and a whole-gene deletion of IDUA (?_-88?)_(*136?)del secondary to maternal somatic mosaicism. We define a previously unreported mutational mechanism for this disorder.
2016: Human Genome Variation
Miki Watanabe, Ryuji Nakagawa, Takuya Naruto, Tomohiro Kohmoto, Ken-Ichi Suga, Aya Goji, Shoji Kagami, Kiyoshi Masuda, Issei Imoto
Ehlers-Danlos syndrome (EDS) is a group of inherited connective tissue disorders characterized by hyperextensible skin, joint hypermobility and soft tissue fragility. For molecular diagnosis, targeted exome sequencing was performed on a 9-year-old male patient who was clinically suspected to have EDS. The patient presented with progressive kyphoscoliosis, joint hypermobility and hyperextensible skin without scars. Ultimately, classical EDS was diagnosed by identifying a novel, mono-allelic mutation in COL5A2 [NM_000393...
2016: Human Genome Variation
Naoya Morisada, Tomoaki Ioroi, Mariko Taniguchi-Ikeda, Ming Juan Ye, Nobuhiko Okamoto, Toshiyuki Yamamoto, Kazumoto Iijima
N-methyl D-aspartate receptor subtype 2B (GluN2B), encoded by GRIN2B, is one of the components of the N-methyl D-aspartate receptor protein. Aberrations in GRIN2B have been reported to be responsible for various types of neurodevelopmental disorders. We report a Japanese boy with an ~2 Mb interstitial deletion in 12p13 involving the entire GRIN2B gene, who presented with intellectual disability, motor developmental delay and marked macrocephaly.
2016: Human Genome Variation
Maryam Rezaei, Ngoc Minh Phuong Nguyen, Leila Foroughinia, Pratima Dash, Fatemeh Ahmadpour, Ishwar Chandra Verma, Rima Slim, Majid Fardaei
Recurrent hydatidiform mole (RHM) is defined by the occurrence of repeated molar pregnancies in affected women. Two genes, NLRP7 and KHDC3L, play a causal role in RHM and are responsible for 48-80% and 5% of cases, respectively. Here, we report the results of screening these two genes for mutations in one Iranian and one Indian patient with RHM. No mutations in NLRP7 were identified in the two patients. KHDC3L sequencing identified two novel protein-truncating mutations in a homozygous state, a 4-bp deletion, c...
2016: Human Genome Variation
Toshiyuki Yamamoto, Keiko Shimojima, Yumiko Ondo, Katsumi Imai, Pin Fee Chong, Ryutaro Kira, Mitsuhiro Amemiya, Akira Saito, Nobuhiko Okamoto
Next-generation sequencing (NGS) is widely used for the detection of disease-causing nucleotide variants. The challenges associated with detecting copy number variants (CNVs) using NGS analysis have been reported previously. Disease-related exome panels such as Illumina TruSight One are more cost-effective than whole-exome sequencing (WES) because of their selective target regions (~21% of the WES). In this study, CNVs were analyzed using data extracted through a disease-related exome panel analysis and the eXome Hidden Markov Model (XHMM)...
2016: Human Genome Variation
Kenichi Takano, Noriko Ogasawara, Tatsuo Matsunaga, Hideki Mutai, Akihiro Sakurai, Aki Ishikawa, Tetsuo Himi
The human noggin (NOG) gene is responsible for a broad spectrum of clinical manifestations of NOG-related symphalangism spectrum disorder (NOG-SSD), which include proximal symphalangism, multiple synostoses, stapes ankylosis with broad thumbs (SABTT), tarsal-carpal coalition syndrome, and brachydactyly type B2. Some of these disorders exhibit phenotypes associated with congenital stapes ankylosis. In the present study, we describe a Japanese pedigree with dactylosymphysis and conductive hearing loss due to congenital stapes ankylosis...
2016: Human Genome Variation
Bushra Rauf, Bushra Irum, Firoz Kabir, Sabika Firasat, Muhammad Asif Naeem, Shaheen N Khan, Tayyab Husnain, Sheikh Riazuddin, Javed Akram, S Amer Riazuddin
Glaucoma is the second leading cause of blindness, affecting ~65 million people worldwide. We identified and ascertained a large cohort of inbred families with multiple individuals manifesting cardinal symptoms of primary congenital glaucoma (PCG) to investigate the etiology of the disease at a molecular level. Ophthalmic examinations, including slit-lamp microscopy and applanation tonometry, were performed to characterize the causal phenotype and confirm that affected individuals fulfilled the diagnostic criteria for PCG...
2016: Human Genome Variation
Naoko Iwasaki, Masashi Tsurumi, Kuniya Asai, Wataru Shimuzu, Atsushi Watanabe, Makiko Ogata, Miho Takizawa, Risa Ide, Toshiyuki Yamamoto, Kayoko Saito
The hepatocyte nuclear factor 1β gene (HNF1B) is responsible for maturity-onset diabetes of the young type 5 (MODY5), which is characterized by early-onset diabetes mellitus and urogenital malformations. HNF1B is expressed during visceral endoderm formation. We identified a disruption of the great pancreatic artery in a patient with MODY5 with no pancreatic body or tail. Our finding supports the significance of HNF1B in the development of the pancreas.
2016: Human Genome Variation
Hong Dang, Paul J Gallins, Rhonda G Pace, Xue-Liang Guo, Jaclyn R Stonebraker, Harriet Corvol, Garry R Cutting, Mitchell L Drumm, Lisa J Strug, Michael R Knowles, Wanda K O'Neal
Published genome-wide association studies (GWASs) identified an intergenic region with regulatory features on chr11p13 associated with cystic fibrosis (CF) lung disease severity. Targeted resequencing in n=377, followed by imputation to n=6,365 CF subjects, was used to identify unrecognized genetic variants (including indels and microsatellite repeats) associated with phenotype. Highly significant associations were in strong linkage disequilibrium and were seen only in Phe508del homozygous CF subjects, indicating a CFTR genotype-specific mechanism...
2016: Human Genome Variation
Hiroyuki Kondo, Itsuka Matsushita, Tatsuo Nagata, Takaaki Hayashi, Masashi Kakinoki, Eiichi Uchio, Mineo Kondo, Masahito Ohji, Shunji Kusaka
Stickler syndrome is an inherited connective tissue disorder that affects the eyes, cartilage and articular tissues. The phenotypes of Stickler syndrome include congenital high myopia, retinal detachment, premature joint degeneration, hearing impairment and craniofacial anomalies, such as cleft palate and midline facial hypoplasia. The disease is genetically heterogeneous, and the majority of the cases are caused by mutations in the COL2A1 gene. We examined 40 Japanese patients with Stickler syndrome from 23 families to determine whether they had mutations in the COL2A1 gene...
2016: Human Genome Variation
Khalid A Fakhro, Michelle R Staudt, Monica Denise Ramstetter, Amal Robay, Joel A Malek, Ramin Badii, Ajayeb Al-Nabet Al-Marri, Charbel Abi Khalil, Alya Al-Shakaki, Omar Chidiac, Dora Stadler, Mahmoud Zirie, Amin Jayyousi, Jacqueline Salit, Jason G Mezey, Ronald G Crystal, Juan L Rodriguez-Flores
Reaching the full potential of precision medicine depends on the quality of personalized genome interpretation. In order to facilitate precision medicine in regions of the Middle East and North Africa (MENA), a population-specific genome for the indigenous Arab population of Qatar (QTRG) was constructed by incorporating allele frequency data from sequencing of 1,161 Qataris, representing 0.4% of the population. A total of 20.9 million single nucleotide polymorphisms (SNPs) and 3.1 million indels were observed in Qatar, including an average of 1...
2016: Human Genome Variation
Taisei Mushiroda, Hideki Yanai, Takashi Yoshiyama, Yuka Sasaki, Masao Okumura, Hideo Ogata, Katsushi Tokunaga
Drug-induced liver injury (DILI) is a common adverse drug reaction in patients receiving antituberculosis (anti-TB) treatment. Among the anti-TB agents, isoniazid (INH) is the primary drug that causes hepatotoxicity in TB patients with DILI. Previous reports in several populations have consistently demonstrated an association between polymorphisms in the N-acetyltransferase 2 (NAT2) gene, which is responsible for INH hepatic metabolism, and a risk of DILI in TB patients. In this study, the genetic and baseline clinical data from 366 Japanese patients with TB (73 patients with DILI and 293 without DILI) were used to develop a system to predict DILI risk due to anti-TB agents...
2016: Human Genome Variation
Ina E Amarillo, Isabelle Nievera, Andrew Hagan, Vishwa Huchthagowder, Jennifer Heeley, Abby Hollander, Joel Koenig, Paul Austin, Ting Wang
Small copy number variations (CNVs) have typically not been analyzed or reported in clinical settings and hence have remained underrepresented in databases and the literature. Here, we focused our investigations on these small CNVs using chromosome microarray analysis (CMA) data previously obtained from patients with atypical characteristics or disorders of sex development (DSD). Using our customized CMA track targeting 334 genes involved in the development of urogenital and reproductive structures and a less stringent analysis filter, we uncovered small genes with recurrent and overlapping CNVs as small as 1 kb, and small regions of homozygosity (ROHs), imprinting and position effects...
2016: Human Genome Variation
Huaichao Luo, Sisi Yu, Ying Lin, Qi Guo, Rongchuan Ma, Zimeng Ye, Yanan Di, Ning Li, Yuanying Miao, Yu Zhou, Yuanfeng Li, Jiyun Yang, Zhenglin Yang
Pseudoachondroplasia (PSACH) is a rare and severe genetic disease; therefore, an accurate molecular diagnosis is essential for appropriate disease treatment and family planning. Currently, the diagnosis of PSACH is based mainly on family history, physical examination and radiographic evaluation. Genetic studies of patients with PSACH in Chinese populations have been very limited. With the application of next-generation sequencing (NGS), a comprehensive molecular diagnosis of PSACH is now possible. The purpose of this study was to perform comprehensive NGS-based molecular diagnoses for patients with PSACH in China...
2016: Human Genome Variation
Chunxia Wang, Katsuhiro Hosono, Shu Kachi, Kimiko Suto, Makoto Nakamura, Hiroko Terasaki, Yozo Miyake, Yoshihiro Hotta, Shinsei Minoshima
Blue cone monochromacy (BCM) is caused by the lack of expression of the normal proteins encoded by the OPN1LW and OPN1MW genes, resulting in the absence of red and green cone sensitivities. We analyzed two cases of BCM in two different families and identified deletion mutations in the locus control region upstream of the two genes. Deletion breakpoints were determined to an accuracy of one base for both cases.
2016: Human Genome Variation
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