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Open AccessArticle

Statistical Dissection of the Genetic Determinants of Phenotypic Heterogeneity in Genes with Multiple Associated Rare Diseases

by Tatyana E. Lazareva, Yury A. Barbitoff, Yulia A. Nasykhova, Nadezhda S. Pavlova, Polina M. Bogaychuk and Andrey S. Glotov

Genes 2023, 14(11), 2100; https://doi.org/10.3390/genes14112100 - 18 Nov 2023

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Abstract

Phenotypicheterogeneity is a phenomenon in which distinct phenotypes can develop in individuals bearing pathogenic variants in the same gene. Genetic factors, gene interactions, and environmental factors are usually considered the key mechanisms of this phenomenon. Phenotypic heterogeneity may impact the prognosis of the [...] Read more.

Phenotypicheterogeneity is a phenomenon in which distinct phenotypes can develop in individuals bearing pathogenic variants in the same gene. Genetic factors, gene interactions, and environmental factors are usually considered the key mechanisms of this phenomenon. Phenotypic heterogeneity may impact the prognosis of the disease severity and symptoms. In our work, we used publicly available data on the association between genetic variants and Mendelian disease to investigate the genetic factors (such as the intragenic localization and type of a variant) driving the heterogeneity of gene–disease relationships. First, we showed that genes linked to multiple rare diseases (GMDs) are more constrained and tend to encode more transcripts with high levels of expression across tissues. Next, we assessed the role of variant localization and variant types in specifying the exact phenotype for GMD variants. We discovered that none of these factors is sufficient to explain the phenomenon of such heterogeneous gene–disease relationships. In total, we identified only 38 genes with a weak trend towards significant differences in variant localization and 30 genes with nominal significant differences in variant type for the two associated disorders. Remarkably, four of these genes showed significant differences in both tests. At the same time, our analysis suggests that variant localization and type are more important for genes linked to autosomal dominant disease. Taken together, our results emphasize the gene-level factors dissecting distinct Mendelian diseases linked to one common gene based on open-access genetic data and highlight the importance of exploring other factors that contributed to phenotypic heterogeneity. Full article

(This article belongs to the Special Issue Genetic and Molecular Basis of Inherited Disorders)

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12 pages, 1530 KiB

Open AccessArticle

FRMD7 Gene Alterations in a Pakistani Family Associated with Congenital Idiopathic Nystagmus

by Muhammad Waqar Arshad, Muhammad Imran Shabbir, Saaim Asif, Mohsin Shahzad, Larissa Leydier and Sunil Kumar Rai

Genes 2023, 14(2), 346; https://doi.org/10.3390/genes14020346 - 29 Jan 2023

Cited by 1 | Viewed by 1976

Abstract

Congenital idiopathic nystagmus (CIN) is an oculomotor disorder characterized by repetitive and rapid involuntary movement of the eye that usually develops in the first six months after birth. Unlike other forms of nystagmus, CIN is widely associated with mutations in the FRMD7 gene. [...] Read more.

Congenital idiopathic nystagmus (CIN) is an oculomotor disorder characterized by repetitive and rapid involuntary movement of the eye that usually develops in the first six months after birth. Unlike other forms of nystagmus, CIN is widely associated with mutations in the FRMD7 gene. This study involves the molecular genetic analysis of a consanguineous Pakistani family with individuals suffering from CIN to undermine any potential pathogenic mutations. Blood samples were taken from affected and normal individuals of the family. Genomic DNA was extracted using an in-organic method. Whole Exome Sequencing (WES) and analysis were performed to find any mutations in the causative gene. To validate the existence and co-segregation of the FRMD7 gene variant found using WES, sanger sequencing was also carried out using primers that targeted all of the FRMD7 coding exons. Additionally, the pathogenicity of the identified variant was assessed using different bioinformatic tools. The WES results identified a novel nonsense mutation in the FRMD7 (c.443T>A; p. Leu148 *) gene in affected individuals from the Pakistani family, with CIN resulting in a premature termination codon, further resulting in the formation of a destabilized protein structure that was incomplete. Co-segregation analysis revealed that affected males are hemizygous for the mutated allele c.443T>A; p. Leu148 * and the affected mother is heterozygous. Overall, such molecular genetic studies expand our current knowledge of the mutations associated with the FRMD7 gene in Pakistani families with CIN and significantly enhance our understanding of the molecular mechanisms involved in genetic disorders. Full article

(This article belongs to the Special Issue Genetic and Molecular Basis of Inherited Disorders)

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19 pages, 2903 KiB

Open AccessArticle

Skin Phototype and Disease: A Comprehensive Genetic Approach to Pigmentary Traits Pleiotropy Using PRS in the GCAT Cohort

by Xavier Farré, Natalia Blay, Beatriz Cortés, Anna Carreras, Susana Iraola-Guzmán and Rafael de Cid

Genes 2023, 14(1), 149; https://doi.org/10.3390/genes14010149 - 05 Jan 2023

Cited by 3 | Viewed by 2653

Abstract

Human pigmentation has largely been associated with different disease prevalence among populations, but most of these studies are observational and inconclusive. Known to be genetically determined, pigmentary traits have largely been studied by Genome-Wide Association Study (GWAS), mostly in Caucasian ancestry cohorts from [...] Read more.

Human pigmentation has largely been associated with different disease prevalence among populations, but most of these studies are observational and inconclusive. Known to be genetically determined, pigmentary traits have largely been studied by Genome-Wide Association Study (GWAS), mostly in Caucasian ancestry cohorts from North Europe, identifying robustly, several loci involved in many of the pigmentary traits. Here, we conduct a detailed analysis by GWAS and Polygenic Risk Score (PRS) of 13 pigmentary-related traits in a South European cohort of Caucasian ancestry (n = 20,000). We observed fair phototype strongly associated with non-melanoma skin cancer and other dermatoses and confirmed by PRS-approach the shared genetic basis with skin and eye diseases, such as melanoma (OR = 0.95), non-melanoma skin cancer (OR = 0.93), basal cell carcinoma (OR = 0.97) and darker phototype with vitiligo (OR = 1.02), cataracts (OR = 1.04). Detailed genetic analyses revealed 37 risk loci associated with 10 out of 13 analyzed traits, and 16 genes significantly associated with at least two pigmentary traits. Some of them have been widely reported, such as MC1R, HERC2, OCA2, TYR, TYRP1, SLC45A2, and some novel candidate genes C1QTNF3, LINC02876, and C1QTNF3-AMACR have not been reported in the GWAS Catalog, with regulatory potential. These results highlight the importance of the assess phototype as a genetic proxy of skin functionality and disease when evaluating open mixed populations. Full article

(This article belongs to the Special Issue Genetic and Molecular Basis of Inherited Disorders)

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28 pages, 8461 KiB

Open AccessArticle

New Insights into the Identity of the DFNA58 Gene

by Larissa Reis do Nascimento, Gleiciele Alice Vieira-Silva, João Paulo Fumio Whitaker Kitajima, Ana Carla Batissoco and Karina Lezirovitz

Genes 2022, 13(12), 2274; https://doi.org/10.3390/genes13122274 - 02 Dec 2022

Cited by 1 | Viewed by 1796

Abstract

Hearing loss is the most common sensory deficit, affecting 466 million people worldwide. The vast and diverse genes involved reflect the complexity of auditory physiology, which requires the use of animal models in order to gain a fuller understanding. Among the loci with [...] Read more.

Hearing loss is the most common sensory deficit, affecting 466 million people worldwide. The vast and diverse genes involved reflect the complexity of auditory physiology, which requires the use of animal models in order to gain a fuller understanding. Among the loci with a yet-to-be validated gene is the DFNA58, in which ~200 Kb genomic duplication, including three protein-coding genes (PLEK, CNRIP1, and PPP3R1′s exon1), was found to segregate with autosomal dominant hearing loss. Through whole genome sequencing, the duplication was found to be in tandem and inserted in an intergenic region, without the disruption of the topological domains. Reanalysis of transcriptomes data studies (zebrafish and mouse), and RT-qPCR analysis of adult zebrafish target organs, in order to access their orthologues expression, highlighted promising results with Cnrip1a, corroborated by zebrafish in situ hybridization and immunofluorescence. Mouse data also suggested Cnrip1 as the best candidate for a relevant role in auditory physiology, and its importance in hearing seems to have remained conserved but the cell type exerting its function might have changed, from hair cells to spiral ganglion neurons. Full article

(This article belongs to the Special Issue Genetic and Molecular Basis of Inherited Disorders)

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13 pages, 2683 KiB

Open AccessArticle

The Identification of Large Rearrangements Involving Intron 2 of the CDH1 Gene in BRCA1/2 Negative and Breast Cancer Susceptibility

by Jihenne Ben Aissa-Haj, Hugo Pinheiro, François Cornelis, Molka Sebai, Didier Meseure, Adrien Briaux, Philippe Berteaux, Cedric Lefol, Gaëtan Des Guetz, Martine Trassard, Denise Stevens, François Vialard, Ivan Bieche, Catherine Noguès, Roseline Tang, Carla Oliveira, Dominique Stoppat-Lyonnet, Rosette Lidereau and Etienne Rouleau

Genes 2022, 13(12), 2213; https://doi.org/10.3390/genes13122213 - 25 Nov 2022

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Abstract

E-cadherin, a CDH1 gene product, is a calcium-dependent cell–cell adhesion molecule playing a critical role in the establishment of epithelial architecture, maintenance of cell polarity, and differentiation. Germline pathogenic variants in the CDH1 gene are associated with hereditary diffuse gastric cancer (HDGC), and [...] Read more.

E-cadherin, a CDH1 gene product, is a calcium-dependent cell–cell adhesion molecule playing a critical role in the establishment of epithelial architecture, maintenance of cell polarity, and differentiation. Germline pathogenic variants in the CDH1 gene are associated with hereditary diffuse gastric cancer (HDGC), and large rearrangements in the CDH1 gene are now being reported as well. Because CDH1 pathogenic variants could be associated with breast cancer (BC) susceptibility, CDH1 rearrangements could also impact it. The aim of our study is to identify rearrangements in the CDH1 gene in 148 BC cases with no BRCA1 and BRCA2 pathogenic variants. To do so, a zoom-in CGH array, covering the exonic, intronic, and flanking regions of the CDH1 gene, was used to screen our cohort. Intron 2 of the CDH1 gene was specifically targeted because it is largely reported to include several regulatory regions. As results, we detected one large rearrangement causing a premature stop in exon 3 of the CDH1 gene in a proband with a bilateral lobular breast carcinoma and a gastric carcinoma (GC). Two large rearrangements in the intron 2, a deletion and a duplication, were also reported only with BC cases without any familial history of GC. No germline rearrangements in the CDH1 coding region were detected in those families without GC and with a broad range of BC susceptibility. This study confirms the diversity of large rearrangements in the CDH1 gene. The rearrangements identified in intron 2 highlight the putative role of this intron in CDH1 regulation and alternative transcripts. Recurrent duplication copy number variations (CNV) are found in this region, and the deletion encompasses an alternative CDH1 transcript. Screening for large rearrangements in the CDH1 gene could be important for genetic testing of BC. Full article

(This article belongs to the Special Issue Genetic and Molecular Basis of Inherited Disorders)

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8 pages, 1091 KiB

Open AccessArticle

Missense Variants in GFRA1 and NPNT Are Associated with Congenital Anomalies of the Kidney and Urinary Tract

by Mohamed H. Al-Hamed, John A. Sayer, Nada Alsahan, Noel Edwards, Wafaa Ali, Maha Tulbah and Faiqa Imtiaz

Genes 2022, 13(10), 1687; https://doi.org/10.3390/genes13101687 - 21 Sep 2022

Cited by 2 | Viewed by 1565

Abstract

The use of next-generation sequencing (NGS) has helped in identifying many genes that cause congenital anomalies of the kidney and urinary tract (CAKUT). Bilateral renal agenesis (BRA) is the most severe presentation of CAKUT, and its association with autosomal recessively inherited genes is [...] Read more.

The use of next-generation sequencing (NGS) has helped in identifying many genes that cause congenital anomalies of the kidney and urinary tract (CAKUT). Bilateral renal agenesis (BRA) is the most severe presentation of CAKUT, and its association with autosomal recessively inherited genes is expanding. Highly consanguineous populations can impact the detection of recessively inherited genes. Here, we report two families harboring homozygous missense variants in recently described genes, NPNT and GFRA1. Two consanguineous families with neonatal death due to CAKUT were investigated. Fetal ultrasound of probands identified BRA in the first family and severe renal cystic dysplasia in the second family. Exome sequencing coupled with homozygosity mapping was performed, and Sanger sequencing was used to confirm segregation of alleles in both families. In the first family with BRA, we identified a homozygous missense variant in GFRA1: c.362A>G; p.(Tyr121Cys), which is predicted to damage the protein structure. In the second family with renal cystic dysplasia, we identified a homozygous missense variant in NPNT: c.56C>G; p.(Ala19Gly), which is predicted to disrupt the signal peptide site. We report two Saudi Arabian consanguineous families with CAKUT phenotypes that included renal agenesis caused by missense variants in GFRA1 and NPNT, confirming the role of these two genes in human kidney development. Full article

(This article belongs to the Special Issue Genetic and Molecular Basis of Inherited Disorders)

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11 pages, 1489 KiB

Open AccessArticle

Identification of New Copy Number Variation and the Evaluation of a CNV Detection Tool for NGS Panel Data in Polish Familial Hypercholesterolemia Patients

by Lena Rutkowska, Iwona Pinkier, Kinga Sałacińska, Łukasz Kępczyński, Dominik Salachna, Joanna Lewek, Maciej Banach, Paweł Matusik, Ewa Starostecka, Andrzej Lewiński, Rafał Płoski, Piotr Stawiński and Agnieszka Gach

Genes 2022, 13(8), 1424; https://doi.org/10.3390/genes13081424 - 10 Aug 2022

Cited by 4 | Viewed by 2366

Abstract

Familial hypercholesterolemia (FH) is an inherited, autosomal dominant metabolic disorder mostly associated with disease-causing variant in LDLR, APOB or PCSK9. Although the dominant changes are small-scale missense, frameshift and splicing variants, approximately 10% of molecularly defined FH cases are due to [...] Read more.

Familial hypercholesterolemia (FH) is an inherited, autosomal dominant metabolic disorder mostly associated with disease-causing variant in LDLR, APOB or PCSK9. Although the dominant changes are small-scale missense, frameshift and splicing variants, approximately 10% of molecularly defined FH cases are due to copy number variations (CNVs). The first-line strategy is to identify possible pathogenic SNVs (single nucleotide variants) using multiple PCR, Sanger sequencing, or with more comprehensive approaches, such as NGS (next-generation sequencing), WES (whole-exome sequencing) or WGS (whole-genome sequencing). The gold standard for CNV detection in genetic diagnostics are MLPA (multiplex ligation-dependent amplification) or aCGH (array-based comparative genome hybridization). However, faster and simpler analyses are needed. Therefore, it has been proposed that NGS data can be searched to analyze CNV variants. The aim of the study was to identify novel CNV changes in FH patients without detected pathogenic SNVs using targeted sequencing and evaluation of CNV calling tool (DECoN) working on gene panel NGS data; the study also assesses its suitability as a screening step in genetic diagnostics. A group of 136 adult and child patients were recruited for the present study. The inclusion criteria comprised at least “possible FH” according to the Simon Broome diagnostic criteria in children and the DLCN (Dutch Lipid Clinical Network) criteria in adults. NGS analysis revealed potentially pathogenic SNVs in 57 patients. Thirty selected patients without a positive finding from NGS were subjected to MLPA analysis; ten of these revealed possibly pathogenic CNVs. Nine patients were found to harbor exons 4–8 duplication, two harbored exons 6–8 deletion and one demonstrated exon 9–10 deletion in LDLR. To test the DECoN program, the whole study group was referred for bioinformatic analysis. The DECoN program detected duplication of exons 4–8 in the LDLR gene in two patients, whose genetic analysis was stopped after the NGS step. The integration of the two methods proved to be particularly valuable in a five-year-old girl presenting with extreme hypercholesterolemia, with both a pathogenic missense variant (c.1747C>T) and exons 9–10 deletion in LDLR. This is the first report of a heterozygous deletion of exons 9 and 10 co-occurring with SNV. Our results suggest that the NGS-based approach has the potential to identify large-scale variation in the LDLR gene and could be further applied to extend CNV screening in other FH-related genes. Nevertheless, the outcomes from the bioinformatic approach still need to be confirmed by MLPA; hence, the latter remains the reference method for assessing CNV in FH patients. Full article

(This article belongs to the Special Issue Genetic and Molecular Basis of Inherited Disorders)

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19 pages, 1439 KiB

Open AccessArticle

A Rare MSH2 Variant as a Candidate Marker for Lynch Syndrome II Screening in Tunisia: A Case of Diffuse Gastric Carcinoma

by Maria Kabbage, Jihenne Ben Aissa-Haj, Houcemeddine Othman, Amira Jaballah-Gabteni, Sarra Laarayedh, Sahar Elouej, Mouna Medhioub, Haifa Tounsi Kettiti, Amal Khsiba, Moufida Mahmoudi, Houda BelFekih, Afifa Maaloul, Hassen Touinsi, Lamine Hamzaoui, Emna Chelbi, Sonia Abdelhak, Mohamed Samir Boubaker and Mohamed Mousaddak Azzouz

Genes 2022, 13(8), 1355; https://doi.org/10.3390/genes13081355 - 28 Jul 2022

Cited by 1 | Viewed by 2206

Abstract

Several syndromic forms of digestive cancers are known to predispose to early-onset gastric tumors such as Hereditary Diffuse Gastric Cancer (HDGC) and Lynch Syndrome (LS). LSII is an extracolonic cancer syndrome characterized by a tumor spectrum including gastric cancer (GC). In the current [...] Read more.

Several syndromic forms of digestive cancers are known to predispose to early-onset gastric tumors such as Hereditary Diffuse Gastric Cancer (HDGC) and Lynch Syndrome (LS). LSII is an extracolonic cancer syndrome characterized by a tumor spectrum including gastric cancer (GC). In the current work, our main aim was to identify the mutational spectrum underlying the genetic predisposition to diffuse gastric tumors occurring in a Tunisian family suspected of both HDGC and LS II syndromes. We selected the index case “JI-021”, which was a woman diagnosed with a Diffuse Gastric Carcinoma and fulfilling the international guidelines for both HDGC and LSII syndromes. For DNA repair, a custom panel targeting 87 candidate genes recovering the four DNA repair pathways was used. Structural bioinformatics analysis was conducted to predict the effect of the revealed variants on the functional properties of the proteins. DNA repair genes panel screening identified two variants: a rare MSH2 c.728G>A classified as a variant with uncertain significance (VUS) and a novel FANCD2 variant c.1879G>T. The structural prediction model of the MSH2 variant and electrostatic potential calculation showed for the first time that MSH2 c.728G>A is likely pathogenic and is involved in the MSH2-MLH1 complex stability. It appears to affect the MSH2-MLH1 complex as well as DNA-complex stability. The c.1879G>T FANCD2 variant was predicted to destabilize the protein structure. Our results showed that the MSH2 p.R243Q variant is likely pathogenic and is involved in the MSH2-MLH1 complex stability, and molecular modeling analysis highlights a putative impact on the binding with MLH1 by disrupting the electrostatic potential, suggesting the revision of its status from VUS to likely pathogenic. This variant seems to be a shared variant in the Mediterranean region. These findings emphasize the importance of testing DNA repair genes for patients diagnosed with diffuse GC with suspicion of LSII and colorectal cancer allowing better clinical surveillance for more personalized medicine. Full article

(This article belongs to the Special Issue Genetic and Molecular Basis of Inherited Disorders)

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0 pages, 2537 KiB

Open AccessCase Report

Non-Invasive Prenatal Test Analysis Opens a Pandora’s Box: Identification of Very Rare Cases of SRY-Positive Healthy Females, Segregating for Three Generations Thanks to Preferential Inactivation of the XqYp Translocated Chromosome

by Cristina Politi, Katia Grillone, Donatella Nocera, Emma Colao, Michelle Li Bellisario, Sara Loddo, Giorgia Catino, Antonio Novelli, Nicola Perrotti, Rodolfo Iuliano and Paola Malatesta

Genes 2024, 15(1), 103; https://doi.org/10.3390/genes15010103 - 16 Jan 2024

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Abstract

The translocation of the testis-determining factor, the SRY gene, from the Y to the X chromosome is a rare event that causes abnormalities in gonadal development. In all cases of males and females carrying this translocation, disorder of sex development is reported. In [...] Read more.

The translocation of the testis-determining factor, the SRY gene, from the Y to the X chromosome is a rare event that causes abnormalities in gonadal development. In all cases of males and females carrying this translocation, disorder of sex development is reported. In our study, we described a peculiar pedigree with the first evidence of four healthy females from three generations who are carriers of the newly identified t(X;Y)(q28;p11.2)(SRY+) translocation with no evidence of ambiguous genitalia or other SRY-dependent alterations. Our study was a consequence of a Non-Invasive Prenatal Test (NIPT) showing a sexual chromosomal abnormality (XXY) followed by a chorionic villus analysis suggesting a normal karyotype 46,XX and t(X;Y) translocation detected by FISH. Here, we (i) demonstrated the inheritance of the translocation in the maternal lineage via karyotyping and FISH analysis; (ii) characterised the structural rearrangement via chromosomal microarray; and (iii) demonstrated, via Click-iT^® EdU Imaging assay, that there was an absolute preferential inactivation of the der(X) chromosome responsible for the lack of SRY expression. Overall, our study provides valuable genetic and molecular information that may lead personal and medical decisions. Full article

(This article belongs to the Special Issue Genetic and Molecular Basis of Inherited Disorders)

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