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Human Genome Variation

Maria Florencia Gosso, Cristian Rohr, Bianca Brun, Guadalupe Mejico, Fernanda Madeira, Fabian Fay, Melina Klurfan, Martin Vazquez
Mowat-Wilson syndrome (MWS) is characterized by severe intellectual disability, absent or impaired speech and microcephaly, with a gradual post-natal onset. The syndrome is often confused with other Angelman-like syndromes (ALS) during infancy, but in older children and adults, the characteristic facial gestalt of Mowat-Wilson syndrome allows it to be distinguished easily from ALS. We report two cases in which an exome-first approach of patients with MWS identified two novel deletions in the ZEB2 gene ranging from a 4 base deletion (case 1) to at least a 573 Kb deletion (case 2)...
2018: Human Genome Variation
Akihiko Ishiyama, Aritoshi Iida, Shinichiro Hayashi, Hirofumi Komaki, Masayuki Sasaki, Ikuya Nonaka, Satoru Noguchi, Ichizo Nishino
LMNA-associated congenital muscular dystrophy (L-CMD) is a severe form of muscle laminopathy. LMNA encodes lamin A, which an intermediate filament protein that attaches to the inner membrane of the nuclear envelope. We performed sequence analysis based on our original targeted gene panel system for muscle diseases to obtain a molecular diagnosis in a Japanese girl with L-CMD. A novel heterozygous missense mutation, c.115A>C (p.Asn39His), in LMNA is reported.
2018: Human Genome Variation
Toshiyuki Yamamoto, Keiko Yamamoto-Shimojima, Yuki Ueda, Katsumi Imai, Yukitoshi Takahashi, Eri Imagawa, Noriko Miyake, Naomichi Matsumoto
Consecutive occurrence of de novo variants in the same family is an extremely rare phenomenon. Two siblings, a younger brother with hypomyelinating leukodystrophy and an elder brother with severe intellectual disability and autistic features, had independent de novo variants of HSPD1 c.139T > G (p.Leu47Val) and HIP1 c.1393G > A (p.Glu465Lys), respectively. These novel variants were predicted to be pathogenic. Both patients also had a known MECP2 variant, c.499C > T (p.Arg167Trp).
2018: Human Genome Variation
Akiko Hida, Shingo Kitamura, Hiroshi Kadotani, Makoto Uchiyama, Takashi Ebisawa, Yuichi Inoue, Yuichi Kamei, Kazuo Mishima
Circadian rhythm sleep-wake disorders (CRSWDs) are characterized by disturbed sleep-wake patterns. We genotyped a PER3 variable number tandem repeat (VNTR) in 248 CRSWD individuals and 925 controls and found no significant association between the VNTR and CRSWDs or morningness-eveningness (diurnal) preferences in the Japanese population. Although the VNTR has been associated with circadian and sleep phenotypes in some other populations, the polymorphism may not be a universal genetic marker.
2018: Human Genome Variation
Nami Araya, Yukitoshi Takahashi, Masayuki Shimono, Tomofumi Fukuda, Mitsuhiro Kato, Mitsuko Nakashima, Naomichi Matsumoto, Hirotomo Saitsu
We report a case of two siblings with progressive myoclonus epilepsy whose parents were not consanguineous. Their clinical symptoms were typical of Lafora disease (LD), but skin biopsies revealed no Lafora bodies. Whole-exome sequencing identified a recurrent homozygous frameshift variant in the NHLRC1 gene in both siblings. The genetic analysis was useful for the diagnosis of LD, as neither consanguinity nor Lafora bodies were found.
2018: Human Genome Variation
Yoshika Akizawa, Toshiyuki Yamamoto, Kazuo Tamura, Toshiyuki Kanno, Nobuko Takahashi, Takeshi Ohki, Teppei Omori, Katsutoshi Tokushige, Masakazu Yamamoto, Kayoko Saito
Lynch syndrome is a genetic disorder related to cancer predisposition, including colorectal cancer, endometrial cancer, and ovarian cancer. Germline mutations in mismatch repair genes, including MLH1 , MSH2 , MSH6 , and PMS2 , are responsible for this condition. Cancer tissue specimens resected from small bowel adenocarcinoma in a Japanese patient showed decreased expression of MLH1 and PMS2 by immunohistochemistry testing. Finally, a novel MLH1 mutation, c.1833dup, was identified in this patient.
2018: Human Genome Variation
Takayuki Yokoi, Yumi Enomoto, Yoshinori Tsurusaki, Takuya Naruto, Kenji Kurosawa
SCN2A mutations are primarily associated with a variety of epilepsy syndromes. Recently, SCN2A has been reported as a gene responsible for nonsyndromic intellectual disability or autism spectrum disorders. Here, we present a case of a 12-year-old girl with nonsyndromic intellectual disability who exhibited a heterozygous de novo missense mutation in SCN2A . She developed seizures during the course of illness. This case suggests that the phenotype of patients with heterozygous SCN2A mutations can be variable...
2018: Human Genome Variation
Andrew T Timberlake, Robin Wu, Carol Nelson-Williams, Charuta G Furey, Kristi I Hildebrand, Scott W Elton, Jeyhan S Wood, John A Persing, Richard P Lifton
Non-syndromic craniosynostosis (CS) affects 1 in 2350 live births. Recent studies have shown that a significant fraction of cases are caused by de novo or rare transmitted mutations that promote premature osteoblast differentiation in cranial sutures. Rare heterozygous loss-of-function (LOF) mutations in SMAD6 and TCF12 are highly enriched in patients with non-syndromic sagittal and coronal CS, respectively. Interestingly, both mutations show striking incomplete penetrance, suggesting a role for modifying alleles; in the case of SMAD6 , a common variant near BMP2 drastically increases penetrance of sagittal CS...
2018: Human Genome Variation
Stephanie L Hines, Anjali Agarwal, Mohamedanwar Ghandour, Aslam Nabeel, Ahmed N Mohammad, Paldeep S Atwal
We report two female patients with focal segmental glomerulosclerosis and chronic kidney disease. The first patient was found to have a heterozygous, de novo, pathogenic variant in COL4A5 (c.141+1G>A, IVS2+1G>A), which is associated with Alport syndrome. The second patient was found to have a heterozygous, likely pathogenic variant in COL4A4 (c.2842G>T). Both these variants in COL4A5 and COL4A4 are novel, and they were detected using whole exome sequencing and gene panel testing, respectively. Additionally, we discuss the complexities of diagnosis in such cases and the benefits of using the abovementioned diagnostic approaches...
2018: Human Genome Variation
Yosuke Ichihashi, Masaki Takagi, Tomohiro Ishii, Kenji Watanabe, Gen Nishimura, Tomonobu Hasegawa
Mutations in the cartilage oligomeric matrix protein ( COMP ) gene cause both pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). Most mutations in COMP are located in the region encoding type 3 thrombospondin like domain (TSP3D). We report two Japanese boys with PSACH who had different novel in-frame deletions in TSP3D. The result recapitulates previous reports in that the in-frame deletions in TSP3D preferentially caused PSACH rather than MED.
2018: Human Genome Variation
Shion Hayashi, Takayuki Yokoi, Chihiro Hatano, Yumi Enomoto, Yoshinori Tsurusaki, Takuya Naruto, Masahisa Kobayashi, Hiroyuki Ida, Kenji Kurosawa
Epidermal growth factor receptor (EGFR), a receptor that recognizes epidermal growth factor, is a very important regulator of cell proliferation and differentiation. To date, three cases of severe ectodermal dysplasia were reported to be caused by an inherited germline homozygous loss-of-function missense mutation of EGFR . This is the first report of a patient with biallelic compound heterozygous mutations in EGFR .
2018: Human Genome Variation
Alessandra Costella, Rossella De Leo, Donatella Guarino, Marco D'Indinosante, Paola Concolino, Giorgia Mazzuccato, Andrea Urbani, Giovanni Scambia, Ettore Capoluongo, Anna Fagotti, Angelo Minucci
In a 72-year-old woman with no associated personal or family history of breast and/or ovarian cancers, we identified a novel somatic pathogenic BRCA2 variant ( c.18_28delAGAGAGGCCAA , p.Lys6Asnfs*4) using next-generation sequencing (NGS). The variant allele frequency (VAF) was 16%, and Sanger sequencing was unable to identify this variant. Adopting a high-resolution melting analysis strategy coupled with NGS, we successfully highlighted the presence of the c.18_28delAGAGAGGCCAA allele.
2018: Human Genome Variation
Michio Inoue, Aritoshi Iida, Shinichiro Hayashi, Madoka Mori-Yoshimura, Atsushi Nagaoka, Shunsuke Yoshimura, Hirokazu Shiraishi, Akira Tsujino, Yuji Takahashi, Ikuya Nonaka, Yukiko K Hayashi, Satoru Noguchi, Ichizo Nishino
VCP mutations were first associated with inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) but was later associated with amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease. Now, a new name, "multisystem proteinopathy (MSP)", is proposed for this condition. VCP encodes valosin-containing protein, which is involved in protein degradation in the ubiquitin proteasome system. We report here two MSP patients with two novel heterozygous missense variants in VCP : c...
2018: Human Genome Variation
Satomi Okano, Akie Miyamoto, Ikue Fukuda, Hajime Tanaka, Kenichiro Hata, Tadashi Kaname, Yoichi Matsubara, Yoshio Makita
Genitopatellar syndrome (GPS) is mainly characterized by an absence of patellae, congenital flexion contractures of the lower limbs, psychomotor retardation, and anomalies of the external genitalia and kidneys. We report an 18-year-old female with a novel heterozygous truncating mutation in exon 17 of the KAT6B gene [MC_000010.11:c.3603_3606 del, p.Arg1201fs]. This is the first report of typical GPS in a Japanese individual. The details of our findings may contribute to elucidating the mechanism underlying GPS-specific clinical features...
2018: Human Genome Variation
Brian P Walcott, Ethan A Winkler, Sirui Zhou, Harjus Birk, Diana Guo, Matthew J Koch, Christopher J Stapleton, Dan Spiegelman, Alexandre Dionne-Laporte, Patrick A Dion, Kristopher T Kahle, Guy A Rouleau, Michael T Lawton
Brain arteriovenous malformations (AVMs) are abnormal connections between arteries and veins that can result in hemorrhagic stroke. A genetic basis for AVMs is suspected, and we investigated potential mutations in a 14-year-old girl who developed a recurrent brain AVM. Whole-exome sequencing (WES) of AVM lesion tissue and blood was performed accompanied by in silico modeling, protein expression observation in lesion tissue and zebrafish modeling. A stop-gain mutation (c.C739T:p.R247X) in the gene SMAD family member 9 ( SMAD9 ) was discovered...
2018: Human Genome Variation
Ahmad Reza Salehi Chaleshtori, Noriko Miyake, Mohammad Ahmadvand, Oranous Bashti, Naomichi Matsumoto, Mehrdad Noruzinia
Inosine is a base located at wobble position 34 of the tRNA anticodon stem-loop, enabling the recognition of more than one codon in the translation process. A heterodimer consists of ADAT3 and ADAT2 and is involved in the adenosine-to-inosine conversion in tRNA. Here, we report the second novel ADAT3 mutation in a patient with microcephaly, intellectual disability, and hyperactivity. These findings constitute a second mutation and expand the clinical spectrum of extremely rare ADAT3 mutations.
2018: Human Genome Variation
Hirokazu Morokawa, Motoko Kamiya, Keiko Wakui, Mikiko Kobayashi, Takashi Kurata, Kazuyuki Matsuda, Rie Kawamura, Hiroyuki Kanno, Yoshimitsu Fukushima, Yozo Nakazawa, Tomoki Kosho
We report on a Japanese female infant as the fourth patient with the constitutional pure duplication 1q41-qter confirmed by chromosomal microarray and as the first who developed myelodysplastic syndrome (MDS) among those with the constitutional 1q duplication. Common clinical features of the constitutional pure duplication 1q41-qter include developmental delay, craniofacial characteristics, foot malformation, hypertrichosis, and respiratory insufficiency. The association between MDS and the duplication of the genes in the 1q41-qter region remains unknown...
2018: Human Genome Variation
Taisuke Sato, Osamu Samura, Noriko Kato, Kosuke Taniguchi, Ken Takahashi, Yuki Ito, Hiroaki Aoki, Masahisa Kobayashi, Ohsuke Migita, Aikou Okamoto, Kenichiro Hata
Branchio-oculo-facial syndrome (BOFS) is a rare autosomal dominant disorder characterized by craniofacial, ocular, and ectodermal anomalies. BOFS is caused by mutation of the transcription factor AP2-alpha gene ( TFAP2A ). We performed detailed genetic analysis of a Japanese family with clinically suspected BOFS and identified a novel missense mutation resulting in a predicted amino-acid substitution in the highly conserved basic DNA-binding domain of TFAP2A (NM_003220.2:c.699A>C).
2018: Human Genome Variation
Yota Sato, Jun Shibasaki, Noriko Aida, Kazuya Hiiragi, Yuichi Kimura, Moe Akahira-Azuma, Yumi Enomoto, Yoshinori Tsurusaki, Kenji Kurosawa
Porencephaly and schizencephaly are congenital brain disorders that can be caused by COL4A1 mutations, though the underlying mechanism and developmental processes are poorly understood. Here, we report a patient with schizencephaly, detected by fetal ultrasonography and fetal magnetic resonance imaging, with a de novo novel mutation in COL4A1 (c.2645_2646delinsAA, p.Gly882Glu). Our results suggest that the onset of damage that potentially results in schizencephaly occurs mid-pregnancy.
2018: Human Genome Variation
Yoshimi Kiyozumi, Hiroyuki Matsubayashi, Yasue Horiuchi, Takuma Oishi, Masato Abe, Sumiko Ohnami, Akane Naruoka, Masatoshi Kusuhara, Ken Yamaguchi
Lynch syndrome, an autosomal dominantly inherited disease, is characterized by an increased risk of developing colorectal cancer. We found a novel germline variant of MLH1 (IVS6+2T>C) that caused Lynch syndrome in a young Japanese patient who had multiple colorectal cancers. Accurate diagnosis will be highly beneficial in clinical practice for surveillance and genetic counseling of patients and their relatives.
2018: Human Genome Variation
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