Candidate Genes in Testing Strategies for Linkage Analysis and Bioinformatic Sorting of Whole Genome Sequencing Data in Three Small Japanese Families with Idiopathic Superior Oblique Muscle Palsy
Idiopathic superior oblique muscle palsy is a major type of paralytic, non-comitant strabismus and presents vertical and cyclo-torsional deviation of one eye against the other eye, with a large vertical fusion range and abnormal head posture such as head tilt. Genetic background is considered to pla...
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MDPI AG
2022-08-01
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| Series: | International Journal of Molecular Sciences |
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| author | Toshihiko Matsuo Chaomulige Mary Miyaji Osamu Hosoya Akira Saito Kazuyuki Nakazono |
| author_facet | Toshihiko Matsuo Chaomulige Mary Miyaji Osamu Hosoya Akira Saito Kazuyuki Nakazono |
| author_sort | Toshihiko Matsuo |
| collection | DOAJ |
| description | Idiopathic superior oblique muscle palsy is a major type of paralytic, non-comitant strabismus and presents vertical and cyclo-torsional deviation of one eye against the other eye, with a large vertical fusion range and abnormal head posture such as head tilt. Genetic background is considered to play a role in its development, as patients with idiopathic superior oblique muscle palsy have varying degrees of muscle hypoplasia and, rarely, the complete absence of the muscle, that is, aplasia. In this study, whole genome sequencing was performed, and single nucleotide variations and short insertions/deletions (SNVs/InDels) were annotated in two patients each in three small families (six patients in total) with idiopathic superior oblique muscle palsy, in addition to three normal individuals in one family. At first, linkage analysis was carried out in the three families and SNVs/InDels in chromosomal loci with negative LOD scores were excluded. Next, SNVs/InDels shared by the six patients, but not by the three normal individuals, were chosen. SNVs/InDels were further narrowed down by choosing low-frequency (<1%) or non-registered SNVs/InDels in four databases for the Japanese population, and then by choosing SNVs/InDels with functional influence, leading to one candidate gene, <i>SSTR5-AS1</i> in chromosome 16. The six patients were heterozygous for 13-nucleotide deletion in <i>SSTR5-AS1</i>, except for one homozygous patient, while the three normal individuals were wild type. Targeted polymerase chain reaction (PCR) and direct sequencing of PCR products confirmed the 13-nucleotide deletion in <i>SSTR5-AS1</i>. In the face of newly-registered <i>SSTR5-AS1</i> 13-nucleotide deletion at a higher frequency in a latest released database for the Japanese population, the skipping of low-frequency and non-registration sorting still resulted in only 13 candidate genes including <i>SSTR5-AS1</i> as common variants. The skipping of linkage analysis also led to the same set of 13 candidate genes. Different testing strategies that consisted of linkage analysis and simple unintentional bioinformatics could reach candidate genes in three small families with idiopathic superior oblique muscle palsy. |
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| language | English |
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| spelling | doaj.art-fd4eddbdf1a34f7eb2817baf37eee79a2023-12-03T12:41:00ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-08-012315862610.3390/ijms23158626Candidate Genes in Testing Strategies for Linkage Analysis and Bioinformatic Sorting of Whole Genome Sequencing Data in Three Small Japanese Families with Idiopathic Superior Oblique Muscle PalsyToshihiko Matsuo0Chaomulige1Mary Miyaji2Osamu Hosoya3Akira Saito4Kazuyuki Nakazono5Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8558, JapanGraduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8558, JapanDepartment of Medical Neurobiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, JapanDepartment of Medical Neurobiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, JapanStaGen Co., Ltd., Tokyo 111-0051, JapanStaGen Co., Ltd., Tokyo 111-0051, JapanIdiopathic superior oblique muscle palsy is a major type of paralytic, non-comitant strabismus and presents vertical and cyclo-torsional deviation of one eye against the other eye, with a large vertical fusion range and abnormal head posture such as head tilt. Genetic background is considered to play a role in its development, as patients with idiopathic superior oblique muscle palsy have varying degrees of muscle hypoplasia and, rarely, the complete absence of the muscle, that is, aplasia. In this study, whole genome sequencing was performed, and single nucleotide variations and short insertions/deletions (SNVs/InDels) were annotated in two patients each in three small families (six patients in total) with idiopathic superior oblique muscle palsy, in addition to three normal individuals in one family. At first, linkage analysis was carried out in the three families and SNVs/InDels in chromosomal loci with negative LOD scores were excluded. Next, SNVs/InDels shared by the six patients, but not by the three normal individuals, were chosen. SNVs/InDels were further narrowed down by choosing low-frequency (<1%) or non-registered SNVs/InDels in four databases for the Japanese population, and then by choosing SNVs/InDels with functional influence, leading to one candidate gene, <i>SSTR5-AS1</i> in chromosome 16. The six patients were heterozygous for 13-nucleotide deletion in <i>SSTR5-AS1</i>, except for one homozygous patient, while the three normal individuals were wild type. Targeted polymerase chain reaction (PCR) and direct sequencing of PCR products confirmed the 13-nucleotide deletion in <i>SSTR5-AS1</i>. In the face of newly-registered <i>SSTR5-AS1</i> 13-nucleotide deletion at a higher frequency in a latest released database for the Japanese population, the skipping of low-frequency and non-registration sorting still resulted in only 13 candidate genes including <i>SSTR5-AS1</i> as common variants. The skipping of linkage analysis also led to the same set of 13 candidate genes. Different testing strategies that consisted of linkage analysis and simple unintentional bioinformatics could reach candidate genes in three small families with idiopathic superior oblique muscle palsy.https://www.mdpi.com/1422-0067/23/15/8626whole genome sequencingidiopathic superior oblique muscle palsystrabismusesotropiaexotropialinkage analysis |
| spellingShingle | Toshihiko Matsuo Chaomulige Mary Miyaji Osamu Hosoya Akira Saito Kazuyuki Nakazono Candidate Genes in Testing Strategies for Linkage Analysis and Bioinformatic Sorting of Whole Genome Sequencing Data in Three Small Japanese Families with Idiopathic Superior Oblique Muscle Palsy International Journal of Molecular Sciences whole genome sequencing idiopathic superior oblique muscle palsy strabismus esotropia exotropia linkage analysis |
| title | Candidate Genes in Testing Strategies for Linkage Analysis and Bioinformatic Sorting of Whole Genome Sequencing Data in Three Small Japanese Families with Idiopathic Superior Oblique Muscle Palsy |
| title_full | Candidate Genes in Testing Strategies for Linkage Analysis and Bioinformatic Sorting of Whole Genome Sequencing Data in Three Small Japanese Families with Idiopathic Superior Oblique Muscle Palsy |
| title_fullStr | Candidate Genes in Testing Strategies for Linkage Analysis and Bioinformatic Sorting of Whole Genome Sequencing Data in Three Small Japanese Families with Idiopathic Superior Oblique Muscle Palsy |
| title_full_unstemmed | Candidate Genes in Testing Strategies for Linkage Analysis and Bioinformatic Sorting of Whole Genome Sequencing Data in Three Small Japanese Families with Idiopathic Superior Oblique Muscle Palsy |
| title_short | Candidate Genes in Testing Strategies for Linkage Analysis and Bioinformatic Sorting of Whole Genome Sequencing Data in Three Small Japanese Families with Idiopathic Superior Oblique Muscle Palsy |
| title_sort | candidate genes in testing strategies for linkage analysis and bioinformatic sorting of whole genome sequencing data in three small japanese families with idiopathic superior oblique muscle palsy |
| topic | whole genome sequencing idiopathic superior oblique muscle palsy strabismus esotropia exotropia linkage analysis |
| url | https://www.mdpi.com/1422-0067/23/15/8626 |
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