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Human Genome Variation

Aritoshi Iida, Eri Takeshita, Shunichi Kosugi, Yoichiro Kamatani, Yukihide Momozawa, Michiaki Kubo, Eiji Nakagawa, Kenji Kurosawa, Ken Inoue, Yu-Ichi Goto
Dandy-Walker malformation (DWM) is a rare congenital malformation defined by hypoplasia of the cerebellar vermis and cystic dilatation of the fourth ventricle. Oligophrenin-1 is mutated in X-linked intellectual disability with or without cerebellar hypoplasia. Here, we report a Japanese DWM patient carrying a novel intragenic 13.5-kb deletion in OPHN1 ranging from exon 11-15. This is the first report of an OPHN1 deletion in a Japanese patient with DWM.
2019: Human Genome Variation
Eliza Courtney, Du Soon Swee, Diana Ishak, Joanne Ngeow
Pallister-Hall syndrome is a rare autosomal dominant condition that is associated with polydactyly and hypothalamic hamartoma and is caused predominantly by frameshift or nonsense pathogenic variants in the GLI3 gene. The majority of cases are identified during childhood; however, rare reports of diagnoses during adulthood exist. Here, we describe the identification of a novel nonsense GLI3 pathogenic variant in an adult male following the incidental detection of a hypothalamic hamartoma.
2018: Human Genome Variation
Tomozumi Takatani, Tadashi Shiohama, Rieko Takatani, Naoki Shimojo
3M syndrome is an autosomal recessive disease characterized by severe pre-natal and post-natal growth retardation, dysmorphic facial features, and skeletal abnormalities. We present a patient with 3M syndrome caused by the compound heterozygous mutations p.Trp68* and p.Gly1452Asp in CUL7 , the latter of which is novel, who exhibited a good body height response to growth hormone treatment. These results expand our knowledge of phenotype-genotype correlations in 3M syndrome, including correlations relevant to growth hormone response...
2018: Human Genome Variation
Yukinori Okada
Quantification of linkage disequilibrium (LD) is a critical step in studies investigating human genome variations. Commonly used LD indices such as r 2 handle LD of biallelic variants for two sites. As shown in a previously introduced LD index of ε , normalized entropy difference of the haplotype frequency between LD and linkage equilibrium (LE) could be utilized to estimate LD of biallelic variants for multiple sites. Here, we developed eLD ( e ntropy-based L inkage D isequilibrium index between multiallelic sites) as publicly available software to calculate ε of multiallelic variants for two sites...
2018: Human Genome Variation
Kaori Irahara-Miyana, Takashi Enokizono, Keiichi Ozono, Norio Sakai
Globoid-cell leukodystrophy is an autosomal-recessive lysosomal storage disorder. Single-base substitutions and small indel mutations in the GALC gene are common in Japanese patients. In this study, we identified three novel deletions, in exons 1, 8, and 11-12, in three patients using Multiplex Ligation-dependent Probe Amplification. We suggest that some patients in whom no or only a single pathogenic mutation is detected by Sanger sequencing may have exon deletions.
2018: Human Genome Variation
Kazumi Takahashi, Takahide Hayano, Ryota Sugimoto, Hirofumi Kashiwagi, Mari Shinoda, Yoshihiro Nishijima, Takahiro Suzuki, Shingo Suzuki, Yuko Ohnuki, Akane Kondo, Takashi Shiina, Hirofumi Nakaoka, Ituro Inoue, Shun-Ichiro Izumi
Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by congenital absence of the vagina and uterus. We conducted genome-wide SNP analyses and exome sequencing to detect the causes of MRKH syndrome. We identified de novo variants of MYCBP2 , NAV3 , and PTPN3 in three families and a variant of MYCBP2 in a sporadic case. Here, we demonstrated the partial genetic makeup of Japanese MRKH syndrome.
2018: Human Genome Variation
Qinan Yin, Kshitij Srivastava, Amha Gebremedhin, Addisalem Taye Makuria, Willy Albert Flegel
The human ACKR1 gene encodes a glycoprotein expressing the Duffy blood group antigens (Fy). The Duffy protein acts as a receptor for distinct pro-inflammatory cytokines and malaria parasites. We determined the haplotypes of the ACKR1 gene in a population inhabiting a malaria-endemic area. We collected blood samples from 60 healthy volunteers in Ethiopia's southwestern low-altitude tropical region. An assay was devised to amplify the ACKR1 gene as a single amplicon and determine its genomic sequence. All haplotypes were resolved at 5178 nucleotides each, covering the coding sequence (CDS) of the ACKR1 gene and including the 5'- and 3'-untranslated regions (UTR), intron 1, and the 5'- and 3'-flanking regions...
2018: Human Genome Variation
Takahiro Ikeda, Hitoshi Osaka, Hiroko Shimbo, Makiko Tajika, Masayo Yamazaki, Ayako Ueda, Kei Murayama, Takanori Yamagata
Approximately 80% of cases of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) harbor a heteroplasmic m.3243A>G transition in the tRNALeu (UUR) ( MTTL1 ) gene. We report a MELAS case with a rare heteroplasmic m.3243A>T mutation found by direct sequencing of MTTL1 . This mutation has been previously reported in 5 cases, of which 2 cases had the MELAS phenotype. Our case also strengthens the hypothesis that the m.3243A>T mutation can cause the MELAS phenotype.
2018: Human Genome Variation
Stephanie L Hines, Anjali Agarwal, Mohamedanwar Ghandour, Nabeel Aslam, Ahmed N Mohammad, Paldeep S Atwal
[This corrects the article DOI: 10.1038/s41439-018-0016-8.].
2018: Human Genome Variation
Satoko Abe, Hidehiko Takeda, Shin-Ya Nishio, Shin-Ichi Usami
EYA4 is a member of the vertebrate eya gene family of transcriptional activators and plays several roles in both embryonic and inner ear development. The majority of EYA4 gene mutations are associated with autosomal dominant non-syndromic hearing loss (DFNA10). In addition, some mutations in this gene cause autosomal dominant syndromic hearing loss with dilated cardiomyopathy. EYA4 is a rare cause of sensorineural hearing loss, and only a limited number of papers regarding mutations in this gene have been published...
2018: Human Genome Variation
Tomoko Lee, Maiko Misaki, Hideki Shimomura, Yasuhiko Tanaka, Satoru Yoshida, Kei Murayama, Kimitoshi Nakamura, Ryoji Fujiki, Osamu Ohara, Hideo Sasai, Toshiyuki Fukao, Yasuhiro Takeshima
An 18-month-old boy was diagnosed with late-onset ornithine transcarbamylase deficiency. Genetic analysis revealed a mosaic frameshift mutation (p.Q279fs) in the OTC gene. Despite the presence of a null mutation, he exhibited a milder phenotype, suggesting that the wild-type allele could rescue the function of OTC. The presence of mosaicism has great effects on the clinical phenotype and recurrence-risk assessment, which should be taken into consideration for genetic counseling.
2018: 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
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