Publications by authors named "Susan H Blanton"

120 Publications

Peripheral vestibular system: Age-related vestibular loss and associated deficits.

J Otol 2021 Oct 11;16(4):258-265. Epub 2021 Jun 11.

University of Miami Miller School of Medicine, Department of Otolaryngology, Miami, FL, USA.

Given the interdependence of multiple factors in age-related vestibular loss (e.g., balance, vision, cognition), it is important to examine the individual contributions of these factors with ARVL. While the relationship between the vestibular and visual systems has been well studied (Bronstein et al., 2015), little is known about the association of the peripheral vestibular system with neurodegenerative disorders (Cronin et al., 2017). Further, emerging research developments implicate the vestibular system as an opportunity for examining brain function beyond balance, and into other areas, such as cognition and psychological functioning. Additionally, the bidirectional impact of psychological functioning is understudied in ARVL. Recognition of ARVL as part of a multifaceted aging process will help guide the development of integrated interventions for patients who remain at risk for decline. In this review, we will discuss a wide variety of characteristics of the peripheral vestibular system and ARVL, how it relates to neurodegenerative diseases, and correlations between ARVL and balance, vision, cognitive, and psychological dysfunction. We also discuss clinical implications as well as future directions for research, with an emphasis on improving care for patients with ARVL.
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http://dx.doi.org/10.1016/j.joto.2021.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438634PMC
October 2021

Application of the ACMG/NSGC genetic referral guidelines for hereditary renal cell carcinoma at the University of Miami, from 2014 to 2017.

Am J Med Genet A 2021 10 21;185(10):3012-3018. Epub 2021 Jun 21.

Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, Florida, USA.

Identifying hereditary syndromes among patients with renal cell carcinoma (RCC) is essential for surveillance of affected individuals and their at-risk family members and for treatment optimization. We conducted a chart review to determine the percentage of patients with RCC who were seen at the University of Miami Health System (UHealth), and met the American College of Medical Genetics (ACMG) and the National Society of Genetic Counselors (NSGC) genetic referral criteria at the University of Miami. Subsequently, we determined the percentage of those who went on to receive genetic evaluation. Patients selected by International Classification of Diseases (ICD) 9/10 codes corresponding to kidney cancer who were at least 18 years of age at the time of diagnosis were included in the study. We included a total of 1443 patients in the final analysis, and after exclusion of charts with incorrect ICD codes, insufficient clinical data, unknown pathology, and patients who were not seen. We used chi-square analysis, ANOVA, and t-test. Of 1443 charts reviewed, 65.7% were male and 34.3% were female. 47.7% self-identified as White, 39.2% as Hispanic, 9.1% as Black, and 4.0% as "other." The mean age of RCC diagnosis was 60.0 ± 12.4 years old. In total, 47.0% of patients met ACMG/NSGC referral criteria for genetic evaluation. Of those, only 4.2% had documented genetic assessment. This study showed a low adherence to ACMG/NSGC genetic referral guidelines at our institution and a need for increasing patients' and practitioners' awareness about the significance of genetic assessment for RCC patients and their family members.
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http://dx.doi.org/10.1002/ajmg.a.62402DOI Listing
October 2021

DNA Methylation Variation Is Identified in Monozygotic Twins Discordant for Non-syndromic Cleft Lip and Palate.

Front Cell Dev Biol 2021 12;9:656865. Epub 2021 May 12.

John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, United States.

Non-syndromic cleft lip with or without cleft palate (NSCLP) is the most common craniofacial birth defect. The etiology of NSCLP is complex with multiple genes and environmental factors playing causal roles. Although studies have identified numerous genetic markers associated with NSCLP, the role of epigenetic variation remains relatively unexplored. Because of their identical DNA sequences, monozygotic (MZ) twins discordant for NSCLP are an ideal model for examining the potential contribution of DNA methylation to non-syndromic orofacial clefting. In this study, we compared the patterns of whole genome DNA methylation in six MZ twin pairs discordant for NSCLP. Differentially methylated positions (DMPs) and regions (DMRs) were identified in NSCLP candidate genes, including differential methylation in and in two independent MZ twin pairs. In addition to DNA methylation differences in NSCLP candidate genes, we found common differential methylation in genes belonging to the Hippo signaling pathway, implicating this mechanosensory pathway in the etiology of NSCLP. The results of this novel approach using MZ twins discordant for NSCLP suggests that differential methylation is one mechanism contributing to NSCLP, meriting future studies on the role of DNA methylation in familial and sporadic NSCLP.
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http://dx.doi.org/10.3389/fcell.2021.656865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149607PMC
May 2021

A nonsense variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder.

Proc Natl Acad Sci U S A 2021 Jun;118(22)

Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.

Genes that are primarily expressed in cochlear glia-like supporting cells (GLSs) have not been clearly associated with progressive deafness. Herein, we present a deafness locus mapped to chromosome 3p25.1 and an auditory neuropathy spectrum disorder (ANSD) gene, , mainly expressed in GLSs. We identify p.(Arg372Ter) of by linkage analysis and exome sequencing in two large Asian families segregating ANSD, which is characterized by inability to discriminate speech despite preserved sensitivity to sound. The knock-in mouse with the p.(Arg372Ter) variant recapitulates a progressive hearing loss with histological abnormalities in GLSs. Mechanistically, TMEM43 interacts with the Connexin26 and Connexin30 gap junction channels, disrupting the passive conductance current in GLSs in a dominant-negative fashion when the p.(Arg372Ter) variant is introduced. Based on these mechanistic insights, cochlear implant was performed on three subjects, and speech discrimination was successfully restored. Our study highlights a pathological role of cochlear GLSs by identifying a deafness gene and its causal relationship with ANSD.
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http://dx.doi.org/10.1073/pnas.2019681118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179140PMC
June 2021

Review of Genotype-Phenotype Correlations in Usher Syndrome.

Ear Hear 2021 May 25. Epub 2021 May 25.

Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida, USA; Dr. John T. Macdonald Foundation Department of Human Genetics, and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA; ENT Institute and Otorhinolaryngology Department of the Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Department of Otolaryngology-Head and Neck Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Unit Progressive Sensory Disorders, Institut Pasteur, Institut de l'Audition, INSERM-UMRS1120, Sorbonne Université, Paris, France; Department of Otolaryngology and Program in Neuroscience, Harvard Medical School and Eaton Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA; and Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida, USA; These authors contributed equally to this work.

Usher syndrome (USH) encompasses a group of clinically and genetically heterogenous disorders defined by the triad of sensorineural hearing loss (SNHL), vestibular dysfunction, and vision loss. USH is the most common cause of deaf blindness. USH is divided clinically into three subtypes-USH1, USH2, and USH3-based on symptom severity, progression, and age of onset. The underlying genetics of these USH forms are, however, significantly more complex, with over a dozen genes linked to the three primary clinical subtypes and other atypical USH phenotypes. Several of these genes are associated with other deaf-blindness syndromes that share significant clinical overlap with USH, pointing to the limits of a clinically based classification system. The genotype-phenotype relationships among USH forms also may vary significantly based on the location and type of mutation in the gene of interest. Understanding these genotype-phenotype relationships and associated natural disease histories is necessary for the successful development and application of gene-based therapies and precision medicine approaches to USH. Currently, the state of knowledge varies widely depending on the gene of interest. Recent studies utilizing next-generation sequencing technology have expanded the list of known pathogenic mutations in USH genes, identified new genes associated with USH-like phenotypes, and proposed algorithms to predict the phenotypic effects of specific categories of allelic variants. Further work is required to validate USH gene causality, and better define USH genotype-phenotype relationships and disease natural histories-particularly for rare mutations-to lay the groundwork for the future of USH treatment.
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http://dx.doi.org/10.1097/AUD.0000000000001066DOI Listing
May 2021

Usher Syndrome in the Inner Ear: Etiologies and Advances in Gene Therapy.

Int J Mol Sci 2021 Apr 10;22(8). Epub 2021 Apr 10.

Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.

Hearing loss is the most common sensory disorder with ~466 million people worldwide affected, representing about 5% of the population. A substantial portion of hearing loss is genetic. Hearing loss can either be non-syndromic, if hearing loss is the only clinical manifestation, or syndromic, if the hearing loss is accompanied by a collage of other clinical manifestations. Usher syndrome is a syndromic form of genetic hearing loss that is accompanied by impaired vision associated with retinitis pigmentosa and, in many cases, vestibular dysfunction. It is the most common cause of deaf-blindness. Currently cochlear implantation or hearing aids are the only treatments for Usher-related hearing loss. However, gene therapy has shown promise in treating Usher-related retinitis pigmentosa. Here we review how the etiologies of Usher-related hearing loss make it a good candidate for gene therapy and discuss how various forms of gene therapy could be applied to Usher-related hearing loss.
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http://dx.doi.org/10.3390/ijms22083910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068832PMC
April 2021

Genetics and the Individualized Therapy of Vestibular Disorders.

Front Neurol 2021 5;12:633207. Epub 2021 Feb 5.

Department of Otolaryngology, University of Miami, Coral Gables, FL, United States.

Vestibular disorders (VDs) are a clinically divergent group of conditions that stem from pathology at the level of the inner ear, vestibulocochlear nerve, or central vestibular pathway. No etiology can be identified in the majority of patients with VDs. Relatively few families have been reported with VD, and so far, no causative genes have been identified despite the fact that more than 100 genes have been identified for inherited hearing loss. Inherited VDs, similar to deafness, are genetically heterogeneous and follow Mendelian inheritance patterns with all modes of transmission, as well as multifactorial inheritance. With advances in genetic sequencing, evidence of familial clustering in VD has begun to highlight the genetic causes of these disorders, potentially opening up new avenues of treatment, particularly in Meniere's disease and disorders with comorbid hearing loss, such as Usher syndrome. In this review, we aim to present recent findings on the genetics of VDs, review the role of genetic sequencing tools, and explore the potential for individualized medicine in the treatment of these disorders. A search of the PubMed database was performed for English language studies relevant to the genetic basis of and therapies for vestibular disorders, using search terms including but not limited to: "genetics," "genomics," "vestibular disorders," "hearing loss with vestibular dysfunction," "individualized medicine," "genome-wide association studies," "precision medicine," and "Meniere's syndrome." Increasing numbers of studies on vestibular disorder genetics have been published in recent years. Next-generation sequencing and new genetic tools are being utilized to unearth the significance of the genomic findings in terms of understanding disease etiology and clinical utility, with growing research interest being shown for individualized gene therapy for some disorders. The genetic knowledge base for vestibular disorders is still in its infancy. Identifying the genetic causes of balance problems is imperative in our understanding of the biology of normal function of the vestibule and the disease etiology and process. There is an increasing effort to use new and efficient genetic sequencing tools to discover the genetic causes for these diseases, leading to the hope for precise and personalized treatment for these patients.
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http://dx.doi.org/10.3389/fneur.2021.633207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892966PMC
February 2021

Screening Consanguineous Families for Hearing Loss Using the MiamiOtoGenes Panel.

Genet Test Mol Biomarkers 2020 Oct 29;24(10):674-680. Epub 2020 Sep 29.

Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida, USA.

Hearing loss (HL) is one of the most common and genetically heterogeneous sensory disorders in humans. Genetic causes underlie 50-60% of all HL and the majority of these cases exhibit an autosomal recessive model of inheritance. In our study, we used our targeted custom MiamiOtoGenes panel of 180 HL-associated genes to screen 23 unrelated consanguineous Iranian families with at least two affected children to identify potential causal variants for HL. We identified pathogenic variants in seven genes (, and ) in nine unrelated families with varying HL profiles. These include five reported and four novel mutations. For small consanguineous families that were unsuitable for conventional linkage analysis the employment of the MiamiOtoGenes panel helped identify the genetic cause of HL in a cost-effective and timely manner. This rapid methodology provides for diagnoses of a significant fraction of HL patients, and identifies those who will need more extensive genetic analyses such as whole exome/genome sequencing.
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http://dx.doi.org/10.1089/gtmb.2020.0153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585618PMC
October 2020

Extreme Phenotype Approach Suggests Taste Transduction Pathway for Carotid Plaque in a Multi-Ethnic Cohort.

Stroke 2020 09 19;51(9):2761-2769. Epub 2020 Aug 19.

Department of Neurology (H.G., C.D., D.D.-M., R.L.S., T.R.), University of Miami, FL.

Background And Purpose: Carotid plaque is a heritable trait and a strong predictor of vascular events. Several loci have been identified for carotid plaque, however, studies in minority populations are lacking. Within a multi-ethnic cohort, we have identified individuals with extreme total carotid plaque area (TCPA), that is, higher or lower TCPA than expected based on traditional vascular risk factors (age, sex, smoking, diabetes mellitus, hypertension, etc). We hypothesized that these individuals are enriched with genetic variants accounting for the plaque burden that cannot be explained by traditional vascular risk factors. Herein, we sought to identify the genetic basis for TCPA using the multi-ethnic cohort.

Methods: Three hundred forty participants (170 from each extreme group) from 3 race/ethnic groups (53% Hispanic, 29% non-Hispanic Black, and 18% non-Hispanic White) were genotyped using a genome-wide single-nucleotide polymorphism (SNP) array and imputed using 1000Genome data. SNP-based analyses using logistic regression and gene-based analyses using VEGAS2 were performed within each race/ethnic group and then meta-analyzed. Genes with <0.001 were included in an overrepresentation enrichment pathway analysis using WebGestalt. Promising findings were tested for association with ischemic stroke using the MEGASTROKE Consortium data set.

Results: No SNP or gene reached genome-wide significance. In the pathway analysis, GO:0050913 (sensory perception of bitter taste) gene set was significantly enriched (=4.5×10, false discovery rate=0.04), which was confirmed in MEGASTROKE (=0.01). Within the GO:0050913 gene set, 3 genes were associated with extreme TCPA in our study (<0.001): , , and . In , rs1376251 is the top SNP and has been associated with myocardial infarction by others. In , a SNP with high regulatory potential (rs3818527, RegulomeScore=1f), and itself were among the top SNP-based and gene-based results and showed consistent evidence for association in all ethnic groups (<0.05).

Conclusions: Extreme TCPA analysis identified new candidate genes for carotid plaque in understudied populations.
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http://dx.doi.org/10.1161/STROKEAHA.120.028979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483772PMC
September 2020

Recent advancements in understanding the role of epigenetics in the auditory system.

Gene 2020 Nov 29;761:144996. Epub 2020 Jul 29.

Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL, USA; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address:

Sensorineural deafness in mammals is most commonly caused by damage to inner ear sensory epithelia, or hair cells, and can be attributed to genetic and environmental causes. After undergoing trauma, many non-mammalian organisms, including reptiles, birds, and zebrafish, are capable of regenerating damaged hair cells. Mammals, however, are not capable of regenerating damaged inner ear sensory epithelia, so that hair cell damage is permanent and can lead to hearing loss. The field of epigenetics, which is the study of various phenotypic changes caused by modification of genetic expression rather than alteration of DNA sequence, has seen numerous developments in uncovering biological mechanisms of gene expression and creating various medical treatments. However, there is a lack of information on the precise contribution of epigenetic modifications in the auditory system, specifically regarding their correlation with development of inner ear (cochlea) and consequent hearing impairment. Current studies have suggested that epigenetic modifications influence differentiation, development, and protection of auditory hair cells in cochlea, and can lead to hair cell degeneration. The objective of this article is to review the existing literature and discuss the advancements made in understanding epigenetic modifications of inner ear sensory epithelial cells. The analysis of the emerging epigenetic mechanisms related to inner ear sensory epithelial cells development, differentiation, protection, and regeneration will pave the way to develop novel therapeutic strategies for hearing loss.
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http://dx.doi.org/10.1016/j.gene.2020.144996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168289PMC
November 2020

COVID19: A Systematic Approach to Early Identification and Healthcare Worker Protection.

Front Public Health 2020 19;8:205. Epub 2020 May 19.

ENT Institute and Otorhinolaryngology Department of the Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.

The COVID-19 outbreak spread rapidly throughout the globe, with worldwide infections and deaths continuing to increase dramatically. To control disease spread and protect healthcare workers, accurate information is necessary. We searched PubMed and Google Scholar for studies published from December 2019 to March 31, 2020 with the terms "COVID-19," "2019-nCoV," "SARS-CoV-2," or "Novel Coronavirus Pneumonia." The main symptoms of COVID-19 are fever (83-98.6%), cough (59.4-82%), and fatigue (38.1-69.6%). However, only 43.8% of patients have fever early in the disease course, despite still being infectious. These patients may present to clinics lacking proper precautions, leading to nosocomial transmission, and infection of workers. Potential COVID-19 cases must be identified early to initiate proper triage and distinguish them quickly from similar infections. Early identification, accurate triage, and standardized personal protection protocols can reduce the risk of cross infection. Containing disease spread will require protecting healthcare workers.
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http://dx.doi.org/10.3389/fpubh.2020.00205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248242PMC
January 2021

Evidence for craniofacial enhancer variation underlying nonsyndromic cleft lip and palate.

Hum Genet 2020 Oct 21;139(10):1261-1272. Epub 2020 Apr 21.

School of Dentistry, Department of Diagnostic and Biomedical Sciences, University of Texas Health Science Center At Houston, 1941 East Road, BBSB 4210, Houston, TX, 77054, USA.

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect for which only ~ 20% of the underlying genetic variation has been identified. Variants in noncoding regions have been increasingly suggested to contribute to the missing heritability. In this study, we investigated whether variation in craniofacial enhancers contributes to NSCLP. Candidate enhancers were identified using VISTA Enhancer Browser and previous publications. Prioritization was based on patterning defects in knockout mice, deletion/duplication of craniofacial genes in animal models and results of whole exome/whole genome sequencing studies. This resulted in 20 craniofacial enhancers to be investigated. Custom amplicon-based sequencing probes were designed and used for sequencing 380 NSCLP probands (from multiplex and simplex families of non-Hispanic white (NHW) and Hispanic ethnicities) using Illumina MiSeq. The frequencies of identified variants were compared to ethnically matched European (CEU) and Los Angeles Mexican (MXL) control genomes and used for association analyses. Variants in mm427/MSX1 and hs1582/SPRY1 showed genome-wide significant association with NSCLP (p ≤ 6.4 × 10). In silico analysis showed that these enhancer variants may disrupt important transcription factor binding sites. Haplotypes involving these enhancers and also mm435/ABCA4 were significantly associated with NSCLP, especially in NHW (p ≤ 6.3 × 10). Importantly, groupwise burden analysis showed several enhancer combinations significantly over-represented in NSCLP individuals, revealing novel NSCLP pathways and supporting a polygenic inheritance model. Our findings support the role of craniofacial enhancer sequence variation in the etiology of NSCLP.
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http://dx.doi.org/10.1007/s00439-020-02169-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487053PMC
October 2020

Diagnostic and therapeutic applications of genomic medicine in progressive, late-onset, nonsyndromic sensorineural hearing loss.

Gene 2020 Jul 15;747:144677. Epub 2020 Apr 15.

Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Human Genetics and John P. Hussman Institute of Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address:

The progressive, late-onset, nonsyndromic, sensorineural hearing loss (PNSHL) is the most common cause of sensory impairment globally, with presbycusis affecting greater than a third of individuals over the age of 65. The etiology underlying PNSHL include presbycusis, noise-induced hearing loss, drug ototoxicity, and delayed-onset autosomal dominant hearing loss (AD PNSHL). The objective of this article is to discuss the potential diagnostic and therapeutic applications of genomic medicine in PNSHL. Genomic factors contribute greatly to PNSHL. The heritability of presbycusis ranges from 25 to 75%. Current therapies for PNSHL range from sound amplification to cochlear implantation (CI). PNSHL is an excellent candidate for genomic medicine approaches as it is common, has well-described pathophysiology, has a wide time window for treatment, and is amenable to local gene therapy by currently utilized procedural approaches. AD PNSHL is especially suited to genomic medicine approaches that can disrupt the expression of an aberrant protein product. Gene therapy is emerging as a potential therapeutic strategy for the treatment of PNSHL. Viral gene delivery approaches have demonstrated promising results in human clinical trials for two inherited causes of blindness and are being used for PNSHL in animal models and a human trial. Non-viral gene therapy approaches are useful in situations where a transient biologic effect is needed or for delivery of genome editing reagents (such as CRISPR/Cas9) into the inner ear. Many gene therapy modalities that have proven efficacious in animal trials have potential to delay or prevent PNSHL in humans. The development of new treatment modalities for PNSHL will lead to improved quality of life of many affected individuals and their families.
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http://dx.doi.org/10.1016/j.gene.2020.144677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244213PMC
July 2020

PBX-WNT-P63-IRF6 pathway in nonsyndromic cleft lip and palate.

Birth Defects Res 2020 02 11;112(3):234-244. Epub 2019 Dec 11.

Department of Pediatrics, University of Texas Health Science Center McGovern Medical School at Houston, Houston, Texas.

Nonsyndromic cleft lip and palate (NSCLP) is one of the most common craniofacial anomalies in humans, affecting more than 135,000 newborns worldwide. NSCLP has a multifactorial etiology with more than 50 genes postulated to play an etiologic role. The genetic pathway comprised of Pbx-Wnt-p63-Irf6 genes was shown to control facial morphogenesis in mice and proposed as a regulatory pathway for NSCLP. Based on these findings, we investigated whether variation in PBX1, PBX2, and TP63, and their proposed interactions were associated with NSCLP. Fourteen single nucleotide variants (SNVs) in/nearby PBX1, PBX2, and TP63 were genotyped in 780 NSCLP families of nonHispanic white (NHW) and Hispanic ethnicities. Family-based association tests were performed for individual SNVs stratified by ethnicity and family history of NSCLP. Gene-gene interactions were also tested. A significant association was found for PBX2 rs3131300 and NSCLP in combined Hispanic families (p = .003) while nominal association was found for TP63 rs9332461 in multiplex Hispanic families (p = .005). Significant haplotype associations were observed for PBX2 in NHW (p = .0002) and Hispanic families (p = .003), and for TP63 in multiplex Hispanic families (.003). An independent case-control group was used to validate findings, and significant associations were found with PBX1 rs6426870 (p = .007) and TP63 rs9332461 (p = .03). Gene-gene interactions were detected between PBX1/PBX2/TP63 with IRF6 in NHW families, and between PBX1 with WNT9B in both NHW and Hispanic families (p < .0018). This study provides the first evidence for a role of PBX1 and PBX2, additional evidence for the role of TP63, and support for the proposed PBX-WNT-TP63-IRF6 regulatory pathway in the etiology of NSCLP.
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http://dx.doi.org/10.1002/bdr2.1630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325739PMC
February 2020

Targeted sequencing of linkage region in Dominican families implicates PRIMA1 and the SPATA7-PTPN21-ZC3H14-EML5-TTC8 locus in carotid-intima media thickness and atherosclerotic events.

Sci Rep 2019 08 12;9(1):11621. Epub 2019 Aug 12.

John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA.

Carotid intima-media thickness (cIMT) is a subclinical marker for atherosclerosis. Previously, we reported a quantitative trait locus (QTL) for total cIMT on chromosome 14q and identified PRiMA1, FOXN3 and CCDC88C as candidate genes using a common variants (CVs)-based approach. Herein, we further evaluated the genetic contribution of the QTL to cIMT by resequencing. We sequenced all exons within the QTL and genomic regions of PRiMA1, FOXN3 and CCDC88C in Dominican families with evidence for linkage to the QTL. Unrelated Dominicans from the Northern Manhattan Study (NOMAS) were used for validation. Single-variant-based and gene-based analyses were performed for CVs and rare variants (RVs). The strongest evidence for association with CVs was found in PRiMA1 (p = 8.2 × 10 in families, p = 0.01 in NOMAS at rs12587586), and in the five-gene cluster SPATA7-PTPN21-ZC3H14-EML5-TTC8 locus (p = 1.3 × 10 in families, p = 0.01 in NOMAS at rs2274736). No evidence for association with RVs was found in PRiMA1. The top marker from previous study in PRiMA1 (rs7152362) was associated with fewer atherosclerotic events (OR = 0.67; p = 0.02 in NOMAS) and smaller cIMT (β = -0.58, p = 2.8 × 10 in Family). Within the five-gene cluster, evidence for association was found for exonic RVs (p = 0.02 in families, p = 0.28 in NOMAS), which was enriched among RVs with higher functional potentials (p = 0.05 in NOMAS for RVs in the top functional tertile). In summary, targeted resequencing provided validation and novel insights into the genetic architecture of cIMT, suggesting stronger effects for RVs with higher functional potentials. Furthermore, our data support the clinical relevance of CVs associated with subclinical atherosclerosis.
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http://dx.doi.org/10.1038/s41598-019-48186-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691113PMC
August 2019

Extrusion pump ABCC1 was first linked with nonsyndromic hearing loss in humans by stepwise genetic analysis.

Genet Med 2019 12 5;21(12):2744-2754. Epub 2019 Jul 5.

Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Purpose: To determine the genetic etiology of deafness in a family (HN-SD01) with autosomal dominant nonsyndromic hearing loss (NSHL).

Methods: Stepwise genetic analysis was performed on family HN-SD01, including hotspot variant screening, exome sequencing, virtual hearing loss gene panel, and genome-wide linkage analysis. Targeted region sequencing was used to screen ABCC1 in additional cases. Cochlear expression of Abcc1 was evaluated by messenger RNA (mRNA) and protein levels. Computational prediction, immunofluorescence, real-time quantitative polymerase chain reaction, and flow cytometry were conducted to uncover functional consequences of candidate variants.

Results: Stepwise genetic analysis identified a heterozygous missense variant, ABCC1:c.1769A>G (p.Asn590Ser), cosegregating with phenotype in HN-SD01. Screening of ABCC1 in an additional 217 cases identified candidate pathogenic variants c.692G>A (p.Gly231Asp) in a sporadic case and c.887A>T (p.Glu296Val) in a familial proband. Abcc1 expressed in stria vascularis and auditory nerve of mouse cochlea. Immunofluorescence showed p.Asn590Ser distributed in cytomembrane and cytoplasm, while wild type was shown only in cytomembrane. Besides, it generated unstable mRNA and decreased efflux capacity of ABCC1.

Conclusion: Stepwise genetic analysis is efficient to analyze the genetic etiology of NSHL. Variants in ABCC1 are linked with NSHL and suggest an important role of extruding pumps in maintaining cochlea function.
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http://dx.doi.org/10.1038/s41436-019-0594-yDOI Listing
December 2019

Genetic screening as an adjunct to universal newborn hearing screening: literature review and implications for non-congenital pre-lingual hearing loss.

Int J Audiol 2019 12 2;58(12):834-850. Epub 2019 Jul 2.

Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL, USA.

Universal newborn hearing screening (UNHS) uses otoacoustic emissions testing (OAE) and auditory brainstem response testing (ABR) to screen all newborn infants for hearing loss (HL), but may not identify infants with mild HL at birth or delayed onset HL. The purpose of this review is to examine the role of genetic screening to diagnose children with pre-lingual HL that is not detected at birth by determining the rate of children who pass UNHS but have a positive genetic screening. This includes a summary of the current UNHS and its limitations and a review of genetic mutations and screening technologies used to detect patients with an increased risk of undiagnosed pre-lingual HL. Literature review of studies that compare UNHS with concurrent genetic screening. Infants and children with HL Sixteen studies were included encompassing 137,895 infants. Pathogenic mutations were detected in 8.66% of patients. In total, 545 patients passed the UNHS but had a positive genetic screening. The average percentage of patients who passed UNHS but had a positive genetic screening was 1.4%. This review demonstrates the positive impact of concurrent genetic screening with UNHS to identify patients with pre-lingual HL.
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http://dx.doi.org/10.1080/14992027.2019.1632499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244215PMC
December 2019

Modifier Gene Candidates in Charcot-Marie-Tooth Disease Type 1A: A Case-Only Genome-Wide Association Study.

J Neuromuscul Dis 2019 ;6(2):201-211

Department for Human Genetics and Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.

Background: Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a uniform 1.5-Mb duplication on chromosome 17p, which includes the PMP22 gene. Patients often present the classic neuropathy phenotype, but also with high clinical variability.

Objective: We aimed to identify genetic variants that are potentially associated with specific clinical outcomes in CMT1A.

Methods: We genotyped over 600,000 genomic markers using DNA samples from 971 CMT1A patients and performed a case-only genome-wide association study (GWAS) to identify potential genetic association in a subset of 644 individuals of European ancestry. A total of 14 clinical outcomes were analyzed in this study.

Results: The analyses yielded suggestive association signals in four clinical outcomes: difficulty with eating utensils (lead SNP rs4713376, chr6 : 30773314, P = 9.91×10-7, odds ratio = 3.288), hearing loss (lead SNP rs7720606, chr5 : 126551732, P = 2.08×10-7, odds ratio = 3.439), decreased ability to feel (lead SNP rs17629990, chr4 : 171224046, P = 1.63×10-7, odds ratio = 0.336), and CMT neuropathy score (lead SNP rs12137595, chr1 : 4094068, P = 1.14×10-7, beta = 3.014).

Conclusions: While the results require validation in future genetic and functional studies, the detected association signals may point to novel genetic modifiers in CMT1A.
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http://dx.doi.org/10.3233/JND-190377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597974PMC
December 2019

Association of IFT88 gene variants with nonsyndromic cleft lip with or without cleft palate.

Birth Defects Res 2019 07 5;111(11):659-665. Epub 2019 Apr 5.

Center for Craniofacial Research, School of Dentistry, University of Texas Health Science Center at Houston, Houston, Texas.

Background: Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect with multifactorial etiology. Genetic studies have identified numerous gene variants in association with NSCLP. IFT88 (intraflagellar transport 88) has been suggested to play a major role in craniofacial development, as Ift88 mutant mice exhibit cleft palate and mutations in IFT88 were identified in individuals with NSCLP.

Objective: To investigate the association of IFT88 single nucleotide gene variants (SNVs) with NSCLP in a large family data set consisting of non-Hispanic white (NHW) and Hispanic families.

Methods: Nine SNVs in/nearby IFT88 were genotyped in 482 NHW families and 301 Hispanic NSCLP families. Genotyping was performed using TaqMan® chemistry. Single- and pairwise-SNV association analyses were performed for all families stratified by ethnicity and family history of NSCLP using the family-based association test (FBAT), and association in the presence of linkage (APL). Bonferroni correction was used to adjust for multiple testing and p values ≤.0055 were considered statistically significant.

Results: Significant association was found between IFT88 rs9509311 and rs2497490 and NSCLP in NHW all families (p = .004 and .005, respectively), while nominal associations were found for rs7998361 and rs9509307 (p < .05). Pairwise association analyses also showed nominal associations between NSCLP in both NHW and Hispanic data sets (p < .05). No association was found between individual variants in IFT88 and NSCLP in Hispanics.

Conclusions: Our results suggest that variation in IFT88 may contribute to NSCLP risk, particularly in multiplex families from a non-Hispanic white population.
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http://dx.doi.org/10.1002/bdr2.1504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227388PMC
July 2019

Variation in SIPA1L2 is correlated with phenotype modification in Charcot- Marie- Tooth disease type 1A.

Ann Neurol 2019 03;85(3):316-330

Department for Human Genetics and Hussman Institute for Human Genomics, University of Miami, Miami, FL.

Objective: Genetic modifiers in rare disease have long been suspected to contribute to the considerable variance in disease expression, including Charcot-Marie-Tooth disease type 1A (CMT1A). To address this question, the Inherited Neuropathy Consortium collected a large standardized sample of such rare CMT1A patients over a period of 8 years. CMT1A is caused in most patients by a uniformly sized 1.5 Mb duplication event involving the gene PMP22.

Methods: We genotyped DNA samples from 971 CMT1A patients on Illumina BeadChips. Genome-wide analysis was performed in a subset of 330 of these patients, who expressed the extremes of a hallmark symptom: mild and severe foot dorsiflexion strength impairment. SIPA1L2 (signal-induced proliferation-associated 1 like 2), the top identified candidate modifier gene, was expressed in the peripheral nerve, and our functional studies identified and confirmed interacting proteins using coimmunoprecipitation analysis, mass spectrometry, and immunocytochemistry. Chromatin immunoprecipitation and in vitro siRNA experiments were used to analyze gene regulation.

Results: We identified significant association of 4 single nucleotide polymorphisms (rs10910527, rs7536385, rs4649265, rs1547740) in SIPA1L2 with foot dorsiflexion strength (p < 1 × 10 ). Coimmunoprecipitation and mass spectroscopy studies identified β-actin and MYH9 as SIPA1L2 binding partners. Furthermore, we show that SIPA1L2 is part of a myelination-associated coexpressed network regulated by the master transcription factor SOX10. Importantly, in vitro knockdown of SIPA1L2 in Schwannoma cells led to a significant reduction of PMP22 expression, hinting at a potential strategy for drug development.

Interpretation: SIPA1L2 is a potential genetic modifier of CMT1A phenotypic expressions and offers a new pathway to therapeutic interventions. ANN NEUROL 2019;85:316-330.
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http://dx.doi.org/10.1002/ana.25426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263419PMC
March 2019

Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting.

Neurology 2019 Jan 16. Epub 2019 Jan 16.

Objective: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.

Methods: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI.

Results: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, = 1.77 × 10; and LINC00539/ZDHHC20, = 5.82 × 10. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits ( value for BI, = 9.38 × 10; = 5.23 × 10 for hypertension), smoking ( = 4.4 × 10; = 1.2 × 10), diabetes ( = 1.7 × 10; = 2.8 × 10), previous cardiovascular disease ( = 1.0 × 10; = 2.3 × 10), stroke ( = 3.9 × 10; = 3.2 × 10), and MRI-defined white matter hyperintensity burden ( = 1.43 × 10; = 3.16 × 10), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI ( ≤ 0.0022), without indication of directional pleiotropy.

Conclusion: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.
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http://dx.doi.org/10.1212/WNL.0000000000006851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369905PMC
January 2019

Dysfunction of , encoding the GRB2-related adaptor protein, is linked to sensorineural hearing loss.

Proc Natl Acad Sci U S A 2019 01 4;116(4):1347-1352. Epub 2019 Jan 4.

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136;

We have identified a variant (c.311A>T; p.Gln104Leu) cosegregating with autosomal recessive nonsyndromic deafness in two unrelated families. encodes a member of the highly conserved growth factor receptor-bound protein 2 (GRB2)/Sem-5/drk family of proteins, which are involved in Ras signaling; however, the function of the growth factor receptor-bound protein 2 (GRB2)-related adaptor protein (GRAP) in the auditory system is not known. Here, we show that, in mouse, is expressed in the inner ear and the protein localizes to the neuronal fibers innervating cochlear and utricular auditory hair cells. Downstream of receptor kinase (), the homolog of human , is expressed in Johnston's organ (JO), the fly hearing organ, and the loss of in JO causes scolopidium abnormalities. mutant flies present deficits in negative geotaxis behavior, which can be suppressed by human wild-type but not mutant GRAP. Furthermore, drk specifically colocalizes with synapsin at synapses, suggesting a potential role of such adaptor proteins in regulating actin cytoskeleton dynamics in the nervous system. Our findings establish a causative link between mutation and nonsyndromic deafness and suggest a function of GRAP/drk in hearing.
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http://dx.doi.org/10.1073/pnas.1810951116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347722PMC
January 2019

Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies.

Nat Commun 2019 01 3;10(1):29. Epub 2019 Jan 3.

Department of Pathology, Erasmus Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.

Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
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http://dx.doi.org/10.1038/s41467-018-07867-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318312PMC
January 2019

FOXF2 is required for cochlear development in humans and mice.

Hum Mol Genet 2019 04;28(8):1286-1297

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.

Molecular mechanisms governing the development of the human cochlea remain largely unknown. Through genome sequencing, we identified a homozygous FOXF2 variant c.325A>T (p.I109F) in a child with profound sensorineural hearing loss (SNHL) associated with incomplete partition type I anomaly of the cochlea. This variant is not found in public databases or in over 1000 ethnicity-matched control individuals. I109 is a highly conserved residue in the forkhead box (Fox) domain of FOXF2, a member of the Fox protein family of transcription factors that regulate the expression of genes involved in embryogenic development as well as adult life. Our in vitro studies show that the half-life of mutant FOXF2 is reduced compared to that of wild type. Foxf2 is expressed in the cochlea of developing and adult mice. The mouse knockout of Foxf2 shows shortened and malformed cochleae, in addition to altered shape of hair cells with innervation and planar cell polarity defects. Expressions of Eya1 and Pax3, genes essential for cochlear development, are reduced in the cochleae of Foxf2 knockout mice. We conclude that FOXF2 plays a major role in cochlear development and its dysfunction leads to SNHL and developmental anomalies of the cochlea in humans and mice.
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http://dx.doi.org/10.1093/hmg/ddy431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452198PMC
April 2019

MPZL2 is a novel gene associated with autosomal recessive nonsyndromic moderate hearing loss.

Hum Genet 2018 Jul 7;137(6-7):479-486. Epub 2018 Jul 7.

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, 1501 NW 10th Avenue, BRB-610 (M-860), Miami, FL, 33136, USA.

While recent studies have revealed a substantial portion of the genes underlying human hearing loss, the extensive genetic landscape has not been completely explored. Here, we report a loss-of-function variant (c.72delA) in MPZL2 in three unrelated multiplex families from Turkey and Iran with autosomal recessive nonsyndromic hearing loss. The variant co-segregates with moderate sensorineural hearing loss in all three families. We show a shared haplotype flanking the variant in our families implicating a single founder. While rare in other populations, the allele frequency of the variant is ~ 0.004 in Ashkenazi Jews, suggesting that it may be an important cause of moderate hearing loss in that population. We show that Mpzl2 is expressed in mouse inner ear, and the protein localizes in the auditory inner and outer hair cells, with an asymmetric subcellular localization. We thus present MPZL2 as a novel gene associated with sensorineural hearing loss.
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http://dx.doi.org/10.1007/s00439-018-1901-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478175PMC
July 2018

BRCA1 and BRCA2 gene variants and nonsyndromic cleft lip/palate.

Birth Defects Res 2018 07 19;110(12):1043-1048. Epub 2018 Jun 19.

Center for Craniofacial Research, UTHealth School of Dentistry at Houston, Houston TX, USA.

Background: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a debilitating condition that not only affects the individual, but the entire family. The purpose of this study was to investigate the association of BRCA1 and BRCA2 genes with NSCL/P.

Methods: Twelve polymorphisms in/nearby BRCA1 and BRCA2 were genotyped using Taqman chemistry. Our data set consisted of 3,473 individuals including 2,191 nonHispanic white (NHW) individuals (from 151 multiplex and 348 simplex families) and 1,282 Hispanic individuals (from 92 multiplex and 216 simplex families). Data analysis was performed using Family-Based Association Test (FBAT), stratified by ethnicity and family history of NSCL/P.

Results: Nominal associations were found between NSCL/P and BRCA1 in Hispanics and BRCA2 in NHW and Hispanics (p < .05). Significant haplotype associations were found between NSCL/P and both BRCA1 and BRCA2 (p ≤ .004).

Conclusions: Our results suggest a modest association between BRCA1 and BRCA2 and NSCL/P. Further studies in additional populations and functional studies are needed to elucidate the role of these genes in developmental processes and signaling pathways contributing to NSCL/P.
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http://dx.doi.org/10.1002/bdr2.1346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105370PMC
July 2018

Knockdown of Crispld2 in zebrafish identifies a novel network for nonsyndromic cleft lip with or without cleft palate candidate genes.

Eur J Hum Genet 2018 10 13;26(10):1441-1450. Epub 2018 Jun 13.

Center for Craniofacial Research, University of Texas Health Science Center at Houston (UTHealth) School of Dentistry, Houston, TX, 77054, USA.

Orofacial development is a multifaceted process involving tightly regulated genetic signaling networks, that when perturbed, lead to orofacial abnormalities including cleft lip and/or cleft palate. We and others have shown an association between the cysteine-rich secretory protein LCCL domain containing 2 (CRISPLD2) gene and nonsyndromic cleft lip with or without cleft palate (NSCLP). Further, we demonstrated that knockdown of Crispld2 in zebrafish alters neural crest cell migration patterns resulting in abnormal jaw and palate development. In this study, we performed RNA profiling in zebrafish embryos and identified 249 differentially expressed genes following knockdown of Crispld2. In silico pathway analysis identified a network of seven genes previously implicated in orofacial development for which differential expression was validated in three of the seven genes (CASP8, FOS, and MMP2). Single nucleotide variant (SNV) genotyping of these three genes revealed significant associations between NSCLP and FOS/rs1046117 (GRCh38 chr14:g.75746690 T > C, p = 0.0005) in our nonHispanic white (NHW) families and MMP2/rs243836 (GRCh38 chr16:g.55534236 G > A; p = 0.002) in our Hispanic families. Nominal association was found between NSCLP and CASP8/rs3769825 (GRCh38 chr2:g.202111380 C > A; p < 0.007). Overtransmission of MMP2 haplotypes were identified in the Hispanic families (p < 0.002). Significant gene-gene interactions were identified for FOS-MMP2 in the NHW families and for CASP8-FOS in the NHW simplex family subgroup (p < 0.004). Additional in silico analysis revealed a novel gene regulatory network including five of these newly identified and 23 previously reported NSCLP genes. Our results demonstrate that animal models of orofacial clefting can be powerful tools to identify novel candidate genes and gene regulatory networks underlying NSCLP.
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http://dx.doi.org/10.1038/s41431-018-0192-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138754PMC
October 2018

A dominant variant in the PDE1C gene is associated with nonsyndromic hearing loss.

Hum Genet 2018 Jul 2;137(6-7):437-446. Epub 2018 Jun 2.

Department of Otolaryngology (D-48), Miller School of Medicine, University of Miami, 1666 NW 12th Avenue, Miami, FL, 33136, USA.

Identification of genes with variants causing non-syndromic hearing loss (NSHL) is challenging due to genetic heterogeneity. The difficulty is compounded by technical limitations that in the past prevented comprehensive gene identification. Recent advances in technology, using targeted capture and next-generation sequencing (NGS), is changing the face of gene identification and making it possible to rapidly and cost-effectively sequence the whole human exome. Here, we characterize a five-generation Chinese family with progressive, postlingual autosomal dominant nonsyndromic hearing loss (ADNSHL). By combining population-specific mutation arrays, targeted deafness genes panel, whole exome sequencing (WES), we identified PDE1C (Phosphodiesterase 1C) c.958G>T (p.A320S) as the disease-associated variant. Structural modeling insights into p.A320S strongly suggest that the sequence alteration will likely affect the substrate-binding pocket of PDE1C. By whole-mount immunofluorescence on postnatal day 3 mouse cochlea, we show its expression in outer (OHC) and inner (IHC) hair cells cytosol co-localizing with Lamp-1 in lysosomes. Furthermore, we provide evidence that the variant alters the PDE1C hydrolytic activity for both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Collectively, our findings indicate that the c.958G>T variant in PDE1C may disrupt the cross talk between cGMP-signaling and cAMP pathways in Ca homeostasis.
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http://dx.doi.org/10.1007/s00439-018-1895-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560636PMC
July 2018

Precision medicine in hearing loss.

J Genet Genomics 2018 02 16;45(2):99-109. Epub 2018 Feb 16.

Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136, USA; John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address:

Precision medicine (PM) proposes customized medical care based on a patient's unique genome, biomarkers, environment and behaviors. Hearing loss (HL) is the most common sensorineural disorder worldwide and is frequently caused by a single genetic mutation. With recent advances in PM tools such as genetic sequencing and data analysis, the field of HL is ideally positioned to adopt the strategies of PM. Here, we review current and future applications of PM in HL as they relate to the four core qualities of PM (P4): predictive, personalized, patient-centered, and participatory. We then introduce a strategy for effective incorporation of HL PM into the design of future research studies, electronic medical records, and clinical practice to improve diagnostics, prognostics, and, ultimately, individualized patient treatment. Finally, specific anticipated ethical and economic concerns in this growing era of genomics-based HL treatment are discussed. By integrating PM principles into translational HL research and clinical practice, hearing specialists are uniquely positioned to effectively treat the heterogeneous causes and manifestations of HL on an individualized basis.
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http://dx.doi.org/10.1016/j.jgg.2018.02.004DOI Listing
February 2018

Genetic basis of hearing loss in Spanish, Hispanic and Latino populations.

Gene 2018 Mar 10;647:297-305. Epub 2018 Jan 10.

Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, China; Tsinghua University School of Medicine, Beijing 10084, China; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address:

Hearing loss (HL) is the most common neurosensory disorder affecting humans. The screening, prevention and treatment of HL require a better understanding of the underlying molecular mechanisms. Genetic predisposition is one of the most common factors that leads to HL. Most HL studies include few Spanish, Hispanic and Latino participants, leaving a critical gap in our understanding about the prevalence, impact, unmet health care needs, and genetic factors associated with hearing impairment among Spanish, Hispanic and Latino populations. The few studies which have been performed show that the gene variants commonly associated with HL in non-Spanish and non-Hispanic populations are infrequently responsible for hearing impairment in Spanish as well as Hispanic and Latino populations (hereafter referred to as Hispanic). To design effective screening tools to detect HL in Spanish and Hispanic populations, studies must be conducted to determine the gene variants that are most commonly associated with hearing impairment in this racial/ethnic group. In this review article, we summarize gene variants and loci associated with HL in Spanish and Hispanic populations. Identifying new genetic variants associated with HL in Spanish and Hispanic populations will pave the way to develop effective screening tools and therapeutic strategies for HL.
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http://dx.doi.org/10.1016/j.gene.2018.01.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806531PMC
March 2018
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