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Human Genome Variation

John E Richter, Hector G Robles, Elizabeth Mauricio, Ahmed Mohammad, Paldeep S Atwal, Thomas R Caulfield
Sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO) is a rare phenotype resulting from pathogenic variants of mitochondrial DNA polymerase gamma ( POLG ). We modeled a novel POLG variant, T599P, that causes the SANDO phenotype and another variant at the same residue, p.T599E, to observe their effect on protein function and confirm the pathogenicity of T599P. Through neoteric molecular modeling techniques, we show that changes at the T599 residue position introduce extra rigidity into the surrounding helix-loop-helix, which places steric pressure on nearby nucleotides...
2018: Human Genome Variation
Nobuhiko Okamoto, Tomohiro Kohmoto, Takuya Naruto, Kiyoshi Masuda, Issei Imoto
Autosomal recessive primary microcephaly (microcephaly primary hereditary, MCPH) is a genetically heterogeneous rare developmental disorder that is characterized by prenatal onset of abnormal brain growth, which leads to intellectual disability of variable severity. We report a 5-year-old male who presented with a severe form of primary microcephaly. Targeted panel sequencing revealed compound heterozygous truncating mutations of the abnormal spindle-like microcephaly-associated ( ASPM ) gene, which confirmed the MCPH5 diagnosis...
2018: Human Genome Variation
Sumito Dateki, Tasuku Kitajima, Toshiharu Kihara, Satoshi Watanabe, Koh-Ichiro Yoshiura, Hiroyuki Moriuchi
The LARP7 gene encodes a chaperone protein of the noncoding RNA 75 K, and mutations in this gene have been identified in patients with Alazami syndrome. Herein, we report another Japanese patient with Alazami syndrome and novel compound heterozygous variants in LARP7 (i.e., c.370delG, p.Glu124fs*38 and c.641_667+25del involving the splice donor site of intron 8). These findings provide further evidence that biallelic LARP7 defects cause the phenotype of Alazami syndrome.
2018: Human Genome Variation
Ayako Ueda, Hiroko Shimbo, Yukari Yada, Yasunori Koike, Takanori Yamagata, Hitoshi Osaka
Pelizaeus-Merzbacher disease (PMD; MIM #312080) is a rare X-linked recessive disorder. A male neonate presented with severe respiratory distress that required tracheostomy. After the appearance of nystagmus, PMD was suspected as a diagnosis for the patient, and a missense mutation, p.Phe51Val, was identified in PLP1 , the gene responsible for PMD. PMD can be a differential diagnosis in a male neonate presenting severe respiratory distress.
2018: Human Genome Variation
Moe Akahira-Azuma, Yoshinori Tsurusaki, Yumi Enomoto, Jun Mitsui, Kenji Kurosawa
We describe an 8-year-old Japanese boy with a de novo recurrent missense mutation in CSNK2A1 , c.593A>G, that is causative of Okur-Chung neurodevelopmental syndrome. He exhibited distinctive facial features, severe growth retardation with relative macrocephaly, and friendly, hyperactive behavior. His dysmorphic features might suggest a congenital histone modification defect syndrome, such as Kleefstra, Coffin-Siris, or Rubinstein-Taybi syndromes, which are indicative of functional interactions between the casein kinase II, alpha 1 gene and histone modification factors...
2018: Human Genome Variation
Samara Arkani, Jia Cao, Johanna Lundin, Daniel Nilsson, Thomas Källman, Gillian Barker, Gundela Holmdahl, Christina Clementsson Kockum, Hans Matsson, Agneta Nordenskjöld
Bladder exstrophy is a congenital closure defect of the urinary bladder with a profound effect on morbidity. Although the malformation is usually sporadic, a genetic background is supported by an increased recurrence risk in relatives, higher concordance rates in monozygotic twins and several associated chromosomal aberrations. Recently, the ISL1 gene was presented as a candidate gene for bladder exstrophy and epispadias complex (BEEC) development in two different studies. In our study, we screened for genetic variants in the ISL1 gene in DNA from 125 Swedish patients using Sanger sequencing and array-CGH analysis...
2018: Human Genome Variation
Shohei Komaki, Yuh Shiwa, Ryohei Furukawa, Tsuyoshi Hachiya, Hideki Ohmomo, Ryo Otomo, Mamoru Satoh, Jiro Hitomi, Kenji Sobue, Makoto Sasaki, Atsushi Shimizu
We launched an integrative multi-omics database, iMETHYL ( iMETHYL provides whole-DNA methylation (~24 million autosomal CpG sites), whole-genome (~9 million single-nucleotide variants), and whole-transcriptome (>14 000 genes) data for CD4+ T-lymphocytes, monocytes, and neutrophils collected from approximately 100 subjects. These data were obtained from whole-genome bisulfite sequencing, whole-genome sequencing, and whole-transcriptome sequencing, making iMETHYL a comprehensive database...
2018: Human Genome Variation
Keiko Shimojima, Nobuhiko Okamoto, Kayo Ohmura, Hiroaki Nagase, Toshiyuki Yamamoto
Recently, haploinsufficiency of PURA has been identified as an essential cause of 5q31.3 microdeletion syndrome, which is characterized by severe psychomotor developmental delay, epilepsy, distinctive features, and delayed myelination. A new 5q31.2-q31.3 microdeletion that included PURA was identified in a patient with infantile spasms. Approximately 50% of patients with PURA -related neurodevelopmental disorders exhibited epilepsy regardless of whether they harbor a 5q31.3 deletion or PURA mutation. Patients with the 5q31...
2018: Human Genome Variation
Yuko Katoh-Fukui, Shuichi Yatsuga, Hirohito Shima, Atsushi Hattori, Akie Nakamura, Kohji Okamura, Kumiko Yanagi, Manami Iso, Tadashi Kaname, Yoichi Matsubara, Maki Fukami
CHARGE syndrome is a rare autosomal dominant disease that is typically caused by heterozygous CHD7 mutations. A de novo variant in a CHD7 splicing acceptor site (NM_017780.3:c.7165-4A>G) was identified in a Japanese boy with CHARGE syndrome. This variant has been considered to be an "unclassified variant" due to its position outside the consensus splicing sites. In this study, abnormal splicing derived from this known variant was confirmed by cDNA sequencing.
2018: Human Genome Variation
Tomohiro Sakaguchi, Tamara Žigman, Danijela Petković Ramadža, Lana Omerza, Silvija Pušeljić, Zrinka Ereš Hrvaćanin, Noriko Miyake, Naomichi Matsumoto, Ivo Barić
Biallelic mutations in the post-GPI attachment to proteins 3 ( PGAP3 ) gene cause hyperphosphatasia with mental retardation syndrome 4 (HPMRS4), which is characterized by elevated serum alkaline phosphatase, severe psychomotor developmental delay, seizures, and facial dysmorphism. To date, 15 PGAP3 mutations have been reported in humans. Here we report a novel homozygous PGAP3 mutation (c.314C>A, p.Pro105Gln) in a Croatian patient and fully describe the clinical features.
2018: Human Genome Variation
Nivedita Hariharan, Samathmika Ravi, Bulagonda Eswarappa Pradeep, Koushik Narayan Subramanyam, Bibha Choudhary, Subhashini Srinivasan, Prakash Khanchandani
A large number of congenital disorders are very rare and localized to rural areas in India, a country that practices both endogamy and consanguinity. Recent advances in genomics can aid in the identification of causative genomic elements when exploring therapeutic interventions and developing neonatal screening to assign novel functions. Here, we report a novel loss-of-function mutation (p.Trp370*) in the HACE1 gene that is associated with a rare congenital neurodevelopmental disorder in a boy from a remote village in southern India...
2018: Human Genome Variation
Akane Yoshikawa, Fumichika Nishimura, Aya Inai, Yosuke Eriguchi, Masaki Nishioka, Atsuhiko Takaya, Mamoru Tochigi, Yoshiya Kawamura, Tadashi Umekage, Kayoko Kato, Tsukasa Sasaki, Kiyoto Kasai, Chihiro Kakiuchi
The mechanism underlying the vulnerability to developing schizophrenia (SCZ) during adolescence remains elusive. Hypofunction of N-methyl-d-aspartate receptors (NMDARs) has been implicated in the pathophysiology of SCZ. During development, the composition of synaptic NMDARs dramatically changes from NR2B-containing NMDARs to NR2A-containing NMDARs through the phosphorylation of NR2B S1480 or Y1472 by CDK5, CSNK2A1, and EphB2, which plays a pivotal role in the maturation of neural circuits. We hypothesized that the dysregulation of developmental change in NMDARs could be involved in the onset of SCZ...
2018: Human Genome Variation
Hiroyuki Akagawa, Maki Mukawa, Tadashi Nariai, Shunsuke Nomura, Yasuo Aihara, Hideaki Onda, Taku Yoneyama, Takumi Kudo, Kazutaka Sumita, Taketoshi Maehara, Takakazu Kawamata, Hidetoshi Kasuya
Moyamoya disease is a progressive steno-occlusive condition of the main intracranial arteries that results in the compensatory formation of fragile moyamoya vessels at the base of the brain. RNF213 is the most significant susceptibility gene and is often found with the p.Arg4810Lys founder variant in East Asian patients. We identified three putatively deleterious variants of this gene from three pediatric patients: two were novel, and one was a recurrent missense variant previously reported in other pediatric patients...
2018: Human Genome Variation
Qiuhong Xiong, Yi Liu, Yu Xue, Shichao Liu, Jing Wang, Ping Li, Changxin Wu, Yanling Yang, Han Xiao
Spondyloepiphyseal dysplasia congenita (SEDC) is an extremely rare autosomal dominant chondrodysplasia that is usually caused by substitution of glycine with another amino acid in the triple helical region of COL2A1. Herein, we describe a case of SEDC in a Chinese family with a novel de novo mutation in the COL2A1 gene, c.1150G>A (p.Gly384Ser), which may impair protein stability and lead to dysfunction of type II collagen.
2018: Human Genome Variation
Giulia Canu, Giorgia Mazzuccato, Andrea Urbani, Angelo Minucci
G6PD deficiency is quite common in Italy where it is characterized by extreme molecular and biochemical heterogeneity. We report a 15-year-old Italian boy with G6PD Nilgiri (c.593G>A, p.Arg198His), a typical Indian variant of the Nilgiris tribal groups. Further, this variant was biochemically characterized, and the molecular screening of the family highlighted a de novo mutational event. To date, this family is the first Caucasian family carrying the G6PD Nilgiri variant.
2018: Human Genome Variation
Junichiro Machida, Hiroaki Goto, Tadashi Tatematsu, Akio Shibata, Hitoshi Miyachi, Katsu Takahashi, Hiroto Izumi, Atsuo Nakayama, Kazuo Shimozato, Yoshihito Tokita
It has been reported that dozens of WNT10A variants are associated with human isolated tooth agenesis, however, little is known about the precise phenotypes. In 50 Japanese patients with severe congenital tooth agenesis, we identified 11 patients with WNT10A variants. Comparing phenotypes between the tooth agenesis patients carrying the wild-type and variants of WNT10A, we revealed that the development of lateral incisors is relatively susceptive to insufficiency of WNT/β-catenin signaling.
2017: Human Genome Variation
Amjad Khan, Rongrong Wang, Shirui Han, Wasim Ahmad, Xue Zhang
Mesoaxial synostotic syndactyly with phalangeal reduction (MSSD) is a rare non-syndromic limb malformation with autosomal recessive inheritance. To date, only a few affected families with MSSD who had BHLHA9 mutations have been reported. The present report describes a consanguineous Pakistani family with five affected individuals with MSSD who exhibited an autosomal recessive pattern. Genotyping followed by Sanger sequencing was performed, and we identified a novel homozygous missense mutation (c.311T>C, p...
2017: Human Genome Variation
Andrew Winegarner, Yoshinori Oie, Satoshi Kawasaki, Nozomi Nishida, Kohji Nishida
An aniridia patient was found to have a novel PAX6 mutation. A genetic duplication within PAX6 , which caused a frameshift mutation, ultimately created a nonsense stop codon and premature truncation of the protein. Consequently, the patient presented with a clouded cornea as a result of partial limbal stem cell deficiency, foveal hypoplasia, nystagmus and a pale, cupped optic disc caused by glaucoma.
2017: Human Genome Variation
Hiroaki Hanafusa, Naoya Morisada, Yusuke Ishida, Ryosuke Sakata, Keiichi Morita, Shizu Miura, Ming Juan Ye, Toshiyuki Yamamoto, Nobuhiko Okamoto, Kandai Nozu, Kazumoto Iijima
The 20q11.2 microdeletion is a rare chromosomal aberration characterized by intellectual disability (ID), motor developmental delay, neonatal feeding problems, and facial dysmorphism. Here, a 2-year- and 6-month-old Japanese girl with a 1.2 Mb microdeletion of 20q11.2 showed ID, motor developmental delay, and distinctive facial features without feeding problems. The deleted region was identified by array-based comparative genomic hybridization and is the smallest reported for a 20q11.2 microdeletion.
2017: Human Genome Variation
Keiko Shimojima, Takafumi Higashiguchi, Kanako Kishimoto, Satoko Miyatake, Noriko Miyake, Jun-Ichi Takanashi, Naomichi Matsumoto, Toshiyuki Yamamoto
The mitochondrial aspartyl-tRNA synthetase 2 gene ( DARS2 ) is responsible for leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL). A Japanese patient with LBSL showed compound heterozygous DARS2 mutations c.358_359delinsTC (p.Gly120Ser) and c.228-15C>G (splicing error). This provides further evidence that most patients with LBSL show compound heterozygous mutations in DARS2 in association with a common splicing mutation in the splicing acceptor site of intron 2.
2017: Human Genome Variation
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