A Study on the Genetics of Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a poorly understood disorder. It is primarily autosomal recessive and is prevalent in tribal communities of the United Arab Emirates due to consanguineous marriages. This retrospective study aimed to assess the pathogenicity of the genetic variants of PCD in indig...

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Autores principales:	Mohammed T. Alsamri, Amnah Alabdouli, Durdana Iram, Alia M. Alkalbani, Ayesha S. Almarzooqi, Abdul-Kader Souid, Ranjit Vijayan
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	genetic counseling Arabian Peninsula primary ciliary dyskinesia respiratory infections sinusitis infertility Medicine R
Acceso en línea:	https://doaj.org/article/2f34656d607d4b7a98c2e5a6db85347b
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spelling	oai:doaj.org-article:2f34656d607d4b7a98c2e5a6db85347b2021-11-11T17:43:25ZA Study on the Genetics of Primary Ciliary Dyskinesia10.3390/jcm102151022077-0383https://doaj.org/article/2f34656d607d4b7a98c2e5a6db85347b2021-10-01T00:00:00Zhttps://www.mdpi.com/2077-0383/10/21/5102https://doaj.org/toc/2077-0383Primary ciliary dyskinesia (PCD) is a poorly understood disorder. It is primarily autosomal recessive and is prevalent in tribal communities of the United Arab Emirates due to consanguineous marriages. This retrospective study aimed to assess the pathogenicity of the genetic variants of PCD in indigenous patients with significant clinical respiratory problems. Pathogenicity scores of variants obtained from the chart review were consolidated using the Ensembl Variant Effect Predictor. The multidimensional dataset of scores was clustered into three groups based on their pathogenicity. Sequence alignment and the Jensen–Shannon Divergence (JSD) were generated to evaluate the amino acid conservation at the site of the variation. One-hundred and twelve variants of 28 genes linked to PCD were identified in 66 patients. Twenty-two variants were double heterozygous, two triple heterozygous, and seven homozygous. Of the thirteen novel variants, two, c.11839 + 1G > A in dynein, axonemal, heavy chain 11 (<i>DNAH11</i>) and p.Lys92Trpfs in dynein, axonemal, intermediate chain 1 (DNAI1) were associated with dextrocardia with situs inversus, and one, p.Gly21Val in coiled-coil domain-containing protein 40 (CCDC40), with absent inner dynein arms. Homozygous <i>C1orf127</i>:p.Arg113Ter (rs558323413) was also associated with laterality defects in two related patients. The majority of variants were missense involving conserved residues with a median JSD score of 0.747. Homology models of two deleterious variants in the stalk of DNAH11, p.Gly3102Asp and p.Leu3127Arg, revealed structural importance of the conserved glycine and leucine. These results define potentially damaging PCD variants in the region. Future studies, however, are needed to fully comprehend the genetic underpinnings of PCD.Mohammed T. AlsamriAmnah AlabdouliDurdana IramAlia M. AlkalbaniAyesha S. AlmarzooqiAbdul-Kader SouidRanjit VijayanMDPI AGarticlegenetic counselingArabian Peninsulaprimary ciliary dyskinesiarespiratory infectionssinusitisinfertilityMedicineRENJournal of Clinical Medicine, Vol 10, Iss 5102, p 5102 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	genetic counseling Arabian Peninsula primary ciliary dyskinesia respiratory infections sinusitis infertility Medicine R
spellingShingle	genetic counseling Arabian Peninsula primary ciliary dyskinesia respiratory infections sinusitis infertility Medicine R Mohammed T. Alsamri Amnah Alabdouli Durdana Iram Alia M. Alkalbani Ayesha S. Almarzooqi Abdul-Kader Souid Ranjit Vijayan A Study on the Genetics of Primary Ciliary Dyskinesia
description	Primary ciliary dyskinesia (PCD) is a poorly understood disorder. It is primarily autosomal recessive and is prevalent in tribal communities of the United Arab Emirates due to consanguineous marriages. This retrospective study aimed to assess the pathogenicity of the genetic variants of PCD in indigenous patients with significant clinical respiratory problems. Pathogenicity scores of variants obtained from the chart review were consolidated using the Ensembl Variant Effect Predictor. The multidimensional dataset of scores was clustered into three groups based on their pathogenicity. Sequence alignment and the Jensen–Shannon Divergence (JSD) were generated to evaluate the amino acid conservation at the site of the variation. One-hundred and twelve variants of 28 genes linked to PCD were identified in 66 patients. Twenty-two variants were double heterozygous, two triple heterozygous, and seven homozygous. Of the thirteen novel variants, two, c.11839 + 1G > A in dynein, axonemal, heavy chain 11 (<i>DNAH11</i>) and p.Lys92Trpfs in dynein, axonemal, intermediate chain 1 (DNAI1) were associated with dextrocardia with situs inversus, and one, p.Gly21Val in coiled-coil domain-containing protein 40 (CCDC40), with absent inner dynein arms. Homozygous <i>C1orf127</i>:p.Arg113Ter (rs558323413) was also associated with laterality defects in two related patients. The majority of variants were missense involving conserved residues with a median JSD score of 0.747. Homology models of two deleterious variants in the stalk of DNAH11, p.Gly3102Asp and p.Leu3127Arg, revealed structural importance of the conserved glycine and leucine. These results define potentially damaging PCD variants in the region. Future studies, however, are needed to fully comprehend the genetic underpinnings of PCD.
format	article
author	Mohammed T. Alsamri Amnah Alabdouli Durdana Iram Alia M. Alkalbani Ayesha S. Almarzooqi Abdul-Kader Souid Ranjit Vijayan
author_facet	Mohammed T. Alsamri Amnah Alabdouli Durdana Iram Alia M. Alkalbani Ayesha S. Almarzooqi Abdul-Kader Souid Ranjit Vijayan
author_sort	Mohammed T. Alsamri
title	A Study on the Genetics of Primary Ciliary Dyskinesia
title_short	A Study on the Genetics of Primary Ciliary Dyskinesia
title_full	A Study on the Genetics of Primary Ciliary Dyskinesia
title_fullStr	A Study on the Genetics of Primary Ciliary Dyskinesia
title_full_unstemmed	A Study on the Genetics of Primary Ciliary Dyskinesia
title_sort	study on the genetics of primary ciliary dyskinesia
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/2f34656d607d4b7a98c2e5a6db85347b
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A Study on the Genetics of Primary Ciliary Dyskinesia

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