Usher syndrome: diagnostic approach, differential diagnoses and proposal of an updated function-based genetic classification

Abstract Usher syndrome (USH) manifests with congenital and apparently isolated hearing loss, followed by retinal degeneration in later life. Therefore, and because of its high prevalence in the congenitally hearing-impaired population, USH is one of the most relevant deafness syndromes. Next-generation sequencing (NGS)-based testing can now provide most analyzed USH patients with a molecular diagnosis, based on mutations in 11 genes. Given the availability of several excellent articles on the clinical and biochemical basis of USH, this short review focuses on critical assessment of new genes announced as USH genes, clinical and genetic differential diagnoses and therapeutic developments. Because obsolete loci, disproved USH genes and the inclusion of genes whose mutations cause similar phenotypes have increasingly blurred genetic classification, a revision based on phenotype restricted to genes related to the Usher protein complex is proposed.

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Next Generation Sequencing Identifies Five Novel Mutations in Lebanese Patients with Bardet–Biedl and Usher Syndromes

Genes ◽

10.3390/genes10121047 ◽

2019 ◽

Vol 10 (12) ◽

pp. 1047 ◽

Cited By ~ 1

Author(s):

Lama Jaffal ◽

Wissam H Joumaa ◽

Alexandre Assi ◽

Charles Helou ◽

George Cherfan ◽

...

Keyword(s):

Next Generation Sequencing ◽

Usher Syndrome ◽

Bioinformatic Analysis ◽

Next Generation ◽

Novel Mutations ◽

Pathogenic Variants ◽

Whole Exome ◽

Targeted Ngs ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

Aim: To identify disease-causing mutations in four Lebanese families: three families with Bardet–Biedl and one family with Usher syndrome (BBS and USH respectively), using next generation sequencing (NGS). Methods: We applied targeted NGS in two families and whole exome sequencing (WES) in two other families. Pathogenicity of candidate mutations was evaluated according to frequency, conservation, in silico prediction tools, segregation with disease, and compatibility with inheritance pattern. The presence of pathogenic variants was confirmed via Sanger sequencing followed by segregation analysis. Results: Most likely disease-causing mutations were identified in all included patients. In BBS patients, we found (M1): c.2258A > T, p. (Glu753Val) in BBS9, (M2): c.68T > C; p. (Leu23Pro) in ARL6, (M3): c.265_266delTT; p. (Leu89Valfs*11) and (M4): c.880T > G; p. (Tyr294Asp) in BBS12. A previously known variant (M5): c.551A > G; p. (Asp184Ser) was also detected in BBS5. In the USH patient, we found (M6): c.188A > C, p. (Tyr63Ser) in CLRN1. M2, M3, M4, and M6 were novel. All of the candidate mutations were shown to be likely disease-causing through our bioinformatic analysis. They also segregated with the corresponding phenotype in available family members. Conclusion: This study expanded the mutational spectrum and showed the genetic diversity of BBS and USH. It also spotlighted the efficiency of NGS techniques in revealing mutations underlying clinically and genetically heterogeneous disorders.

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Proteogenomics and its applications in biology and precision medicine

Vietnam Journal of Biotechnology ◽

10.15625/1811-4989/15386 ◽

2021 ◽

Vol 19 (1) ◽

pp. 1-14

Author(s):

Phan Van Chi ◽

Le Thi Bich Thao

Keyword(s):

Mass Spectrometry ◽

Precision Medicine ◽

Open Reading Frames ◽

Biological Processes ◽

New Genes ◽

Fundamental Research ◽

Diagnostic Research ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing ◽

Reading Frames

In this review, we briefly discuss proteogenomics, the integration of proteomics with genomics and transcriptomics, whereby the underlying technologies are next-generation sequencing (NGS) and mass spectrometry (MS) with processing the resulting data, an emerging field that promises to accelerate fundamental research related to transcription and translation, as well as its applicability. By combining genomic and proteomic information, scientists are achieving new results due to a more complete and unified understanding of complex molecular biological processes. Part of this review introduces some of the results of using proteogenomics in solving problems such as annotation, gene/genome re-annotation, including editing of open reading frames (ORFs), or improving a process to detect new genes in a number of different organisms, including humans. In particular, the paper also discusses the potential of proteogenomics through research achievements on human genome/proteome in precision medicine, especially in projects on phylogenetic and diagnostic research. and cancer treatment. The challenges and future of proteogenomics are also discussed and documented.

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ERBB2 Pathway in Biliary Tract Carcinoma: Clinical Implications of a Targetable Pathway

Oncology Research and Treatment ◽

10.1159/000511919 ◽

2020 ◽

pp. 1-8

Author(s):

Oded Jacobi ◽

Jeffrey S. Ross ◽

Tal Goshen-Lago ◽

Riad Haddad ◽

Assaf Moore ◽

...

Keyword(s):

Median Overall Survival ◽

Tissue Samples ◽

Genomic Landscape ◽

High Prevalence ◽

Before And After ◽

Disease Stabilization ◽

Poor Outcomes ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing ◽

Copy Number Amplification

Background/Aims: Current chemotherapy regimens for cholangiocarcinoma (CCA) yield poor outcomes, with a median overall survival of <12 months. Recent data on the genomic landscape of CCAs have created opportunities for targeted therapy. Yet, data regarding its efficacy are scarce. We aimed to describe the genomic landscape of a CCA patient cohort using next-generation sequencing (NGS), focusing on the ERBB/EFGR pathway and assessing response to anti-HER2 agents. Methods: Tissue samples of intrahepatic CCA (IHCC) and extrahepatic CCA (EHCC) underwent NGS for somatic aberrations. The clinical outcomes for patients treated with anti-HER2 agents were evaluated. Results: A total of 1,863 CCA cases (1,615 IHCCs and 248 EHCCs) underwent NGS, and they revealed a high prevalence of ERBB alterations (IHCC, 4.2%; EHCC, 9.7%). Among these, 23.8% of the IHCCs and 53.6% of the EHCCs had a point mutation in ERBB2, and 66.6% of the IHCCs and 41.2% of the EHCCs had ERBB copy number amplification. Three EHCC patients were diagnosed at our institute with ERBB/EGFR aberrations; 2 patients were treated with neratinib and 1 patient with a chemotherapy-trastuzumab combination. All 3 achieved disease stabilization and a clinical benefit. One patient underwent a liquid biopsy before and after 3 months of treatment, demonstrating disappearance of the ERBB2 clone and emergence of a Myc-mutated clone after treatment. Conclusions: The genomic landscape of CCAs may harbor targetable alterations, especially in the ERBB/EGFR pathway. These alterations may have clinical significance in everyday practice.

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OR15-03 High Prevalence of Gene Variants in Boys of Prepubertal Age with Clinical Suspicion of Central Hypogonadism and Low AMH

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1462 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Franco Brunello ◽

E Gabriela Sansó ◽

Paula Scaglia ◽

María Esnaola Azcoiti ◽

Ariel Berenstein ◽

...

Keyword(s):

Genetic Diagnosis ◽

Clinical Suspicion ◽

Gene Variants ◽

High Prevalence ◽

History Of ◽

Potential Pathogenicity ◽

Next Generation Sequencing Ngs ◽

Prepubertal Age ◽

Generation Sequencing ◽

Low Serum

Abstract Introduction: In boys of prepubertal age, the diagnosis of central hypogonadism may be difficult to ascertain since gonadotropins and testosterone are normally low. Sertoli cell markers, like AMH and inhibin B, may be useful. In recent years, with the development of next generation sequencing (NGS) technology, the number of genes associated with central hypogonadism has had an exponential increase. However, even with these advanced techniques, the gene variants with potential pathogenicity can be found at present in only 30-50% of the patients. Hypothesis of the study: Low serum AMH is an appropriate screening biomarker to select patients for NGS, in order to make a genetic diagnosis in boys of prepubertal age with suspected central hypogonadism. Patients and methods: All patients aged 1-10 yr referred between 2001 and 2018 with clinical suspicion of central hypogonadism (micropenis and cryptorchidism and/or microorchidism), with low serum AMH (<10th centile) were included. Serum AMH was determined by ELISA (Beckman-Coulter), and LH, FSH and testosterone (T) by ECLIA (Roche). NGS was performed with the TruSight™ One Sequencing Panel in a NextSeq® 500 sequencer (Illumina). Results are expressed as medians (range). Results: 13 patients were included. Age at first visit was 4.4 (0.1-9.2) yr. Cryptorchidism was present in all of them, micropenis in 10 and microorchidism in 11. Orchiopexy was required in 11 boys and the other 2 responded to hCG treatment. 4 patients had olfactory disturbances, 1 had sensory deafness and 1 had piebaldism. 2 patients had a family history of olfactory disturbances and/or central hypogonadism. 7 patients could be followed up to pubertal age, and the diagnosis of central hypogonadism was clinically confirmed. At age 6.1 yr (1.2-10), AMH was 159 pmol/L (65-363), LH was <0.1 IU/L in all, FSH was 0.61 IU/L (<0.1-1.9). 17 variants in 9 genes associated with central hypogonadism were found in 10 of 13 patients. 5 boys had 1 gene variant, while 4 had 2 gene variants and 1 had 3 gene variants indicating probable oligogenicity, in the following genes: FGFR1 (n:4), CHD7 (n:3), PROKR2 (n:2), SOX10 (n:2), AXL (n:2), HS6ST1 (n:1), AMHR2 (n:1), NSMF (n:1), DCC (n:1). Conclusion: A high prevalence of gene variants was found in boys of prepubertal age with a suspicion of central hypogonadism based on micropenis and cryptorchidism and/or microorchidism with low serum AMH.

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Genetics of Primary Ovarian Insufficiency in the Next-Generation Sequencing Era

Journal of the Endocrine Society ◽

10.1210/jendso/bvz037 ◽

2019 ◽

Vol 4 (2) ◽

Cited By ~ 7

Author(s):

Monica Malheiros França ◽

Berenice Bilharinho Mendonca

Keyword(s):

Next Generation Sequencing ◽

Web Of Science ◽

Follicle Stimulating Hormone ◽

Primary Ovarian Insufficiency ◽

Next Generation ◽

Genetic Etiology ◽

Ovarian Insufficiency ◽

New Genes ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

Abstract Primary ovarian insufficiency (POI) is characterized by amenorrhea, increased follicle-stimulating hormone (FSH) levels, and hypoestrogenism, leading to infertility before the age of 40 years. Elucidating the cause of POI is a key point for diagnosing and treating affected women. Here, we review the genetic etiology of POI, highlighting new genes identified in the last few years using next-generation sequencing (NGS) approaches. We searched the MEDLINE/PubMed, Cochrane, and Web of Science databases for articles published in or translated to English. Several genes were found to be associated with POI genetic etiology in humans and animal models (SPIDR, BMPR2, MSH4, MSH5, GJA4, FANCM, POLR2C, MRPS22, KHDRBS1, BNC1, WDR62, ATG7/ATG9, BRCA2, NOTCH2, POLR3H, and TP63). The heterogeneity of POI etiology has been revealed to be remarkable in the NGS era, and discoveries have indicated that meiosis and DNA repair play key roles in POI development.

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High prevalence of co-infecting enteropathogens in suspected rotavirus vaccine breakthrough cases

Journal of Clinical Microbiology ◽

10.1128/jcm.01236-21 ◽

2021 ◽

Author(s):

Ceren Simsek ◽

Mandy Bloemen ◽

Daan Jansen ◽

Leen Beller ◽

Patrick Descheemaeker ◽

...

Keyword(s):

Giardia Lamblia ◽

Epidemiological Studies ◽

Viral Metagenomics ◽

Rotavirus Vaccine ◽

Breakthrough Infection ◽

Reverse Transcription Pcr ◽

Rotavirus Vaccines ◽

High Prevalence ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

Despite the global use of rotavirus vaccines, vaccine breakthrough cases remain a pediatric health problem. In this study, we investigated suspected rotavirus vaccine breakthrough cases using next-generation sequencing (NGS) based viral metagenomics (n=102) and a panel of semi-quantitative reverse transcription PCR (RT-qPCR) (n=92) targeting known enteric pathogens. Overall, we identified co-infections in 80% of the cases. Enteropathogens such as Adenovirus (32%), Enterovirus (15%), diarrheagenic Escherichia coli (1-14%), Astrovirus (10%), Blastocystis spp. (10%), Parechovirus (9%), Norovirus (9%), Clostridium difficile (9%), Dientamoeba fragilis (9%), Sapovirus (8%), Campylobacter jejuni (4%) and Giardia lamblia (4%) were detected. Except for a few reassortant rotavirus strains, unusual genotypes or genotype combinations were not present. However, in addition to well-known enteric viruses, divergent variants of enteroviruses and non-classic astroviruses were identified using NGS. We estimated that in 31.5% of the patients, rotavirus was likely not the cause of gastroenteritis and in 14.1% of the patients, it contributed together with another pathogen(s) to disease. The remaining 54.4% of the patients likely had a ‘true vaccine breakthrough infection’. The high prevalence of alternative enteropathogens in the suspected rotavirus vaccine breakthrough cases suggests that gastroenteritis is often the result of a co-infection, and the rotavirus vaccine effectiveness might be underestimated in clinical and epidemiological studies.

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