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Functional Studies of Genetic Variants Involved in Human Genetic Diseases
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Functional Studies of Genetic Variants Involved in Human Genetic Diseases

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 May 2023) | Viewed by 12552

Special Issue Editors

Dr. Muhammad Umair

E-Mail Website
Guest Editor
Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia
Interests: rare genetic disorders; human molecular genetics; functional studies; novel gene identification; genomics; rare diseases; genotype–phenotype correlations
Dr. Ahmed Waqas

E-Mail Website
Guest Editor
Department Zoology, Division of Science and Technology, University of Education Lahore, Punjab, Pakistan
Interests: rare genetic disorders; functional studies using animal models; data analysis; diagnosis
Dr. Muhammad Muaaz Aslam

E-Mail Website
Guest Editor Assistant
Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
Interests: genetics of complex diseases; genetics of Alzheimer’s disease and related dementia; cognitive decline; bioinformatics; statistical analysis; genetics of autoimmune diseases; Down syndrome; rheumatoid arthritis

Special Issue Information

Dear Colleagues,

The technological advancements in nucleic acid sequencing platforms, such as next-generation sequencing (NGS) and massively parallel sequencing, resulted in the identification of novel candidate genes and sequence variants across human genomes.

The massive amounts of sequencing data helped develop global online analyses and patient disease databases, thus enabling researchers to identify and examine genetic errors across the genome, transcriptome, and proteome.

The human genome data helped identify rare sequence variants, helping us understand functions, their effects on human phenotypes, and disease management, thus greatly influencing human health. However, the precise mechanisms underlying pathophysiology remain elusive for most genetic disorders.

Identifying specific genetic and physiological contributions to heritable disorders potentiates early interventions; targeted, more effective treatments; the anticipation of comorbidities; and counseling parents on prognoses and recurrence risks.

We encourage submissions of unpublished, original manuscripts (research articles, reviews, case reports, and communications) with a solid genetic component describing recent advances in all aspects related, but not limited, to the following topics: functional studies on genes or variants; gene expression analyses; rare variant analyses; animal models; iPSCs; clinical and molecular descriptions of new syndromic and non-syndromic forms of genetic disorders; clinical and molecular descriptions of congenital defects in prenatal and postnatal periods; and genotype–phenotype correlations.

Dr. Muhammad Umair
Dr. Ahmed Waqas
Guest Editors

Dr. Muhammad Muaaz Aslam
Guest Editor Assistant

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • rare variant analyses
  • rare genetic disorders
  • functional studies
  • genotype–phenotype correlations

Published Papers (6 papers)

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Research

18 pages, 2300 KiB  
Article
Biallelic Variants in Seven Different Genes Associated with Clinically Suspected Bardet–Biedl Syndrome
by Hamed Nawaz, Mujahid, Sher Alam Khan, Farhana Bibi, Ahmed Waqas, Abdul Bari, Fardous, Niamatullah Khan, Nazif Muhammad, Amjad Khan, Sohail Aziz Paracha, Qamre Alam, Mohammad Azhar Kamal, Misbahuddin M. Rafeeq, Noor Muhammad, Fayaz Ul Haq, Shazia Khan, Arif Mahmood, Saadullah Khan and Muhammad Umair
Genes 2023, 14(5), 1113; https://doi.org/10.3390/genes14051113 - 19 May 2023
Cited by 3 | Viewed by 1819
Abstract
Bardet–Biedl syndrome (BBS) is a rare clinically and genetically heterogeneous autosomal recessive multi-systemic disorder with 22 known genes. The primary clinical and diagnostic features include six different hallmarks, such as rod–cone dystrophy, learning difficulties, renal abnormalities, male hypogonadism, post-axial polydactyly, and obesity. Here, [...] Read more.
Bardet–Biedl syndrome (BBS) is a rare clinically and genetically heterogeneous autosomal recessive multi-systemic disorder with 22 known genes. The primary clinical and diagnostic features include six different hallmarks, such as rod–cone dystrophy, learning difficulties, renal abnormalities, male hypogonadism, post-axial polydactyly, and obesity. Here, we report nine consanguineous families and a non-consanguineous family with several affected individuals presenting typical clinical features of BBS. In the present study, 10 BBS Pakistani families were subjected to whole exome sequencing (WES), which revealed novel/recurrent gene variants, including a homozygous nonsense mutation (c.94C>T; p.Gln32Ter) in the IFT27 (NM_006860.5) gene in family A, a homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B, a homozygous nonsense variant (c.720C>A; p.Cys240Ter) in the WDPCP (NM_015910.7) in family C, a homozygous nonsense variant (c.505A>T; p.Lys169Ter) in the LZTFL1 (NM_020347.4) in family D, pathogenic homozygous 1 bp deletion (c.775delA; p.Thr259Leufs*21) in the MKKS/BBS5 (NM_170784.3) gene in family E, a pathogenic homozygous missense variant (c.1339G>A; p.Ala447Thr) in BBS1 (NM_024649.4) in families F and G, a pathogenic homozygous donor splice site variant (c.951+1G>A; p?) in BBS1 (NM_024649.4) in family H, a pathogenic bi-allelic nonsense variant in MKKS (NM_170784.3) (c.119C>G; p.Ser40*) in family I, and homozygous pathogenic frameshift variants (c.196delA; p.Arg66Glufs*12) in BBS5 (NM_152384.3) in family J. Our findings extend the mutation and phenotypic spectrum of four different types of ciliopathies causing BBS and also support the importance of these genes in the development of multi-systemic human genetic disorders. Full article
(This article belongs to the Special Issue Functional Studies of Genetic Variants Involved in Human Genetic Diseases)
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14 pages, 2642 KiB  
Article
A Novel Homozygous Nonsense Variant in the DYM Underlies Dyggve-Melchior-Clausen Syndrome in Large Consanguineous Family
by Abu Bakar, Sulaiman Shams, Nousheen Bibi, Asmat Ullah, Wasim Ahmad, Musharraf Jelani, Osama Yousef Muthaffar, Angham Abdulrhman Abdulkareem, Turki S. Abujamel, Absarul Haque, Muhammad Imran Naseer and Bushra Khan
Genes 2023, 14(2), 510; https://doi.org/10.3390/genes14020510 - 17 Feb 2023
Cited by 1 | Viewed by 1854
Abstract
(1) Background: Dyggve-Melchior-Clausen Syndrome is a skeletal dysplasia caused by a defect in the DYM gene (OMIM number 607461). Pathogenic variants in the gene have been reported to cause Dyggve-Melchior-Clausen (DMC; OMIM 223800) dysplasia and Smith-McCort (SMC; OMIM 607326) dysplasia. (2) Methods: In [...] Read more.
(1) Background: Dyggve-Melchior-Clausen Syndrome is a skeletal dysplasia caused by a defect in the DYM gene (OMIM number 607461). Pathogenic variants in the gene have been reported to cause Dyggve-Melchior-Clausen (DMC; OMIM 223800) dysplasia and Smith-McCort (SMC; OMIM 607326) dysplasia. (2) Methods: In the present study, large consanguineous families with five affected individuals with osteochondrodysplasia phenotypes were recruited. The family members were analyzed by polymerase chain reaction for homozygosity mapping using highly polymorphic microsatellite markers. Subsequent to linkage analysis, the coding exons and exon intron border of the DYM gene were amplified. The amplified products were then sent for Sanger sequencing. The structural effect of the pathogenic variant was analyzed by different bioinformatics tools. (3) Results: Homozygosity mapping revealed a 9 Mb homozygous region on chromosome 18q21.1 harboring DYM shared by all available affected individuals. Sanger sequencing of the coding exons and exon intron borders of the DYM gene revealed a novel homozygous nonsense variant [DYM (NM_017653.6):c.1205T>A, p.(Leu402Ter)] in affected individuals. All the available unaffected individuals were either heterozygous or wild type for the identified variant. The identified mutation results in loss of protein stability and weekend interactions with other proteins making them pathogenic (4) Conclusions: This is the second nonsense mutation reported in a Pakistani population causing DMC. The study presented would be helpful in prenatal screening, genetic counseling, and carrier testing of other members in the Pakistani community. Full article
(This article belongs to the Special Issue Functional Studies of Genetic Variants Involved in Human Genetic Diseases)
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12 pages, 1547 KiB  
Article
Homozygous Missense Variant in the Solute Carrier Organic Anion Transporter 2A1 (SLCO2A1) Gene Underlies Isolated Nail Clubbing
by Muhammad Umair, Muhammad Bilal, Khadim Shah, Gulab Said and Farooq Ahmad
Genes 2023, 14(2), 430; https://doi.org/10.3390/genes14020430 - 8 Feb 2023
Cited by 3 | Viewed by 1700
Abstract
Background: Inherited isolated nail clubbing is a very rare Mendelian condition in humans, characterized by enlargement of the terminal segments of fingers and toes with thickened nails. Mutations in two genes have been reported to cause isolated nail clubbing in humans, which are [...] Read more.
Background: Inherited isolated nail clubbing is a very rare Mendelian condition in humans, characterized by enlargement of the terminal segments of fingers and toes with thickened nails. Mutations in two genes have been reported to cause isolated nail clubbing in humans, which are the SLCO2A1 gene and the HPGD gene. Objectives: An extended Pakistani family having two affected siblings born of unaffected consanguineous union was included in the study. Predominant isolated congenital nail clubbing (ICNC) without any other systemic abnormalities was observed, which we aimed to characterize at clinico-genetic level. Methods: Whole exome coupled with Sanger sequencing were employed to uncover the sequence variant as a cause of the disease. Furthermore, protein modeling was carried out to reveal the predicted possible effect of the mutation at the protein level. Results: Whole exome sequencing data analysis revealed a novel biallelic sequence variant (c.155T>A; p.Phe52Tyr) in the SLCO2A1 gene. Further, Sanger sequencing analysis validated and confirmed the segregation of the novel variant in the entire family. Subsequently, protein modeling of the wild-type and mutated SLCO2A1 revealed broad-scale change, which might compromise the proteins’ secondary structure and function. Conclusion: The present study adds another mutation to the SLCO2A1-related pathophysiology. The involvement of SLCO2A1 in the pathogenesis of ICNC may open exciting perceptions of this gene in nail development/morphogenesis. Full article
(This article belongs to the Special Issue Functional Studies of Genetic Variants Involved in Human Genetic Diseases)
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19 pages, 2741 KiB  
Article
Functional Analyses of Rare Germline Missense BRCA1 Variants Located within and outside Protein Domains with Known Functions
by Henrikke Nilsen Hovland, Eunice Kabanyana Mchaina, Hildegunn Høberg-Vetti, Sarah Louise Ariansen, Wenche Sjursen, Marijke Van Ghelue, Bjørn Ivar Haukanes, Per Morten Knappskog, Ingvild Aukrust and Elisabet Ognedal
Genes 2023, 14(2), 262; https://doi.org/10.3390/genes14020262 - 19 Jan 2023
Cited by 2 | Viewed by 1719
Abstract
The BRCA1 protein is implicated in numerous important cellular processes to prevent genomic instability and tumorigenesis, and pathogenic germline variants predispose carriers to hereditary breast and ovarian cancer (HBOC). Most functional studies of missense variants in BRCA1 focus on variants located within the [...] Read more.
The BRCA1 protein is implicated in numerous important cellular processes to prevent genomic instability and tumorigenesis, and pathogenic germline variants predispose carriers to hereditary breast and ovarian cancer (HBOC). Most functional studies of missense variants in BRCA1 focus on variants located within the Really Interesting New Gene (RING), coiled-coil and BRCA1 C-terminal (BRCT) domains, and several missense variants in these regions have been shown to be pathogenic. However, the majority of these studies focus on domain specific assays, and have been performed using isolated protein domains and not the full-length BRCA1 protein. Furthermore, it has been suggested that BRCA1 missense variants located outside domains with known function are of no functional importance, and could be classified as (likely) benign. However, very little is known about the role of the regions outside the well-established domains of BRCA1, and only a few functional studies of missense variants located within these regions have been published. In this study, we have, therefore, functionally evaluated the effect of 14 rare BRCA1 missense variants considered to be of uncertain clinical significance, of which 13 are located outside the well-established domains and one within the RING domain. In order to investigate the hypothesis stating that most BRCA1 variants located outside the known protein domains are benign and of no functional importance, multiple protein assays including protein expression and stability, subcellular localisation and protein interactions have been performed, utilising the full-length protein to better mimic the native state of the protein. Two variants located outside the known domains (p.Met297Val and p.Asp1152Asn) and one variant within the RING domain (p.Leu52Phe) were found to make the BRCA1 protein more prone to proteasome-mediated degradation. In addition, two variants (p.Leu1439Phe and p.Gly890Arg) also located outside known domains were found to have reduced protein stability compared to the wild type protein. These findings indicate that variants located outside the RING, BRCT and coiled-coiled domains could also affect the BRCA1 protein function. For the nine remaining variants, no significant effects on BRCA1 protein functions were observed. Based on this, a reclassification of seven variants from VUS to likely benign could be suggested. Full article
(This article belongs to the Special Issue Functional Studies of Genetic Variants Involved in Human Genetic Diseases)
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11 pages, 2544 KiB  
Article
Report of Hermansky–Pudlak Syndrome in Two Families with Novel Variants in HPS3 and HPS4 Genes
by Qaiser Zaman, Sadeeda, Muhammad Anas, Gauhar Rehman, Qadeem Khan, Aiman Iftikhar, Mashal Ahmad, Muhammad Owais, Ilyas Ahmad, Osama Yousef Muthaffar, Angham Abdulrhman Abdulkareem, Fehmida Bibi, Musharraf Jelani and Muhammad Imran Naseer
Genes 2023, 14(1), 145; https://doi.org/10.3390/genes14010145 - 5 Jan 2023
Cited by 4 | Viewed by 2327
Abstract
Background: Hermansky–Pudlak syndrome (HSP) was first reported in 1959 as oculocutaneous albinism with bleeding abnormalities, and now consists of 11 distinct heterogenic genetic disorders that are caused by mutations in four protein complexes: AP-3, BLOC1, BLOC2, and BLOC3. Most of the patients show [...] Read more.
Background: Hermansky–Pudlak syndrome (HSP) was first reported in 1959 as oculocutaneous albinism with bleeding abnormalities, and now consists of 11 distinct heterogenic genetic disorders that are caused by mutations in four protein complexes: AP-3, BLOC1, BLOC2, and BLOC3. Most of the patients show albinism and a bleeding diathesis; additional features may present depending on the nature of a defective protein complex. The subtypes 3 and 4 have been known for mutations in HSP3 and HSP4 genes, respectively. Methods: In this study, two Pakhtun consanguineous families, ALB-09 and ALB-10, were enrolled for clinical and molecular diagnoses. Whole-exome sequencing (WES) of the index patient in each family followed by Sanger sequencing of all available samples was performed using 3Billion. Inc South Korea rare disease diagnostics services. Results: The affected individuals of families ALB-09 and ALB-10 showed typical phenotypes of HPS such as oculocutaneous albinism, poor vision, nystagmus, nystagmus-induced involuntary head nodding, bleeding diathesis, and enterocolitis; however, immune system weakness was not recorded. WES analyses of one index patient revealed a novel nonsense variant (NM_032383.4: HSP3; c.2766T > G) in family ALB-09 and a five bp deletion (NM_001349900.2: HSP4; c.1180_1184delGTTCC) variant in family ALB-10. Sanger sequencing confirmed homozygous segregation of the disease alleles in all affected individuals of the respective family. Conclusions: The substitution c.2766T > G creates a premature protein termination at codon 922 in HPS3, replacing tyrosine amino acid with a stop codon (p.Tyr922Ter), while the deletion mutation c.1180_1184delGTTCC leads to a reading frameshift and a premature termination codon adding 23 abnormal amino acids to HSP4 protein (p:Val394Pro395fsTer23). To the best of our knowledge, the two novel variants identified in HPS3 and HPS4 genes causing Hermansky–Pudlak syndrome are the first report from the Pakhtun Pakistani population. Our work expands the pathogenic spectrum of HPS3 and HPS4 genes, provides successful molecular diagnostics, and helps the families in genetic counselling and reducing the disease burden in their future generations. Full article
(This article belongs to the Special Issue Functional Studies of Genetic Variants Involved in Human Genetic Diseases)
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12 pages, 3171 KiB  
Article
The Expansion of the Spectrum in Stuttering Disorders to a Novel ARMC Gene Family (ARMC3)
by Adil U Rehman, Malaika Hamid, Sher Alam Khan, Muhammad Eisa, Wasim Ullah, Zia Ur Rehman, Muzammil Ahmad Khan, Sulman Basit, Noor Muhammad, Saadullah Khan and Naveed Wasif
Genes 2022, 13(12), 2299; https://doi.org/10.3390/genes13122299 - 6 Dec 2022
Cited by 1 | Viewed by 1715
Abstract
Stuttering is a common neurodevelopment speech disorder that negatively affects the socio-psychological dimensions of people with disability. It displays many attributes of a complex genetic trait, and a few genetic loci have been identified through linkage studies. Stuttering is highly variable regarding its [...] Read more.
Stuttering is a common neurodevelopment speech disorder that negatively affects the socio-psychological dimensions of people with disability. It displays many attributes of a complex genetic trait, and a few genetic loci have been identified through linkage studies. Stuttering is highly variable regarding its phenotypes and molecular etiology. However, all stutters have some common features, including blocks in speech, prolongation, and repetition of sounds, syllables, and words. The involuntary actions associated with stuttering often involve increased eye blinking, tremors of the lips or jaws, head jerks, clenched fists, perspiration, and cardiovascular changes. In the present study, we recruited a consanguineous Pakistani family showing an autosomal recessive mode of inheritance. The exome sequencing identified a homozygous splice site variant in ARMC3 (Armadillo Repeat Containing 3) in a consanguineous Pashtun family of Pakistani origin as the underlying genetic cause of non-syndromic stuttering. The homozygous splice site variant (NM_173081.5:c.916 + 1G > A) segregated with the stuttering phenotype in this family. The splice change leading to the skipping of exon-8 is a loss of function (LoF) variant, which is predicted to undergo NMD (Nonsense mediated decay). Here, we report ARMC3 as a novel candidate gene causing the stuttering phenotype. ARMC3 may lead to neurodevelopmental disorders, including stuttering in humans. Full article
(This article belongs to the Special Issue Functional Studies of Genetic Variants Involved in Human Genetic Diseases)
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