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Suzanne M Leal

Publications and source records attributed to Suzanne M Leal.

At least 19 recordsLinked to original sources
PubMed2025

Exome sequencing revealed a novel homozygous variant in TRMT61 A in a multiplex family with atypical Cornelia de Lange Syndrome from Rwanda.

BACKGROUND: In 30% of patients who exhibit the clinical profile of Cornelia de Lange Syndrome (CdLS), the genetic cause remains undetermined. This proportion tends to be higher in low-resource settings including Africa. We performed a molecular characterization of CdLS in a multiplex Rwandan family. METHODS: After a clinical evaluation of two affected siblings, DNA isolated from peripheral whole blood of the affected patients and their parents underwent Exome Sequencing (ES). Sanger sequencing validated the variant segregating with CdLS. In silico predictive tools, protein modelling, and cell-based experiments using HEK293T cells were used to investigate the pathogenicity of the variant found. RESULTS: We identified a family with two parents and their two offspring (male and female), who were referred for hearing impairment. The 17-year-old female presented bilateral profound hearing impairment with moderate hypertelorism, progressive visual impairment, and secondary amenorrhea. The 14-year-old male displayed intellectual disability and a bilateral profound hearing impairment with no noticeable facial dysmorphism. Following exome sequencing (ES) of DNA samples obtained from the four family members, we found that the siblings harbored a novel likely pathogenic homozygous missense variant in the TRMT61 A gene [NM_152307.3:c.665C > T p.(Ala222Val)] inherited from both heterozygous parents. In silico analysis suggested that the variant substitutes a highly conserved amino acid, and 2-D structure modelling revealed a significant decrease in the stability of the protein. Cell-based experiment in HEK293T showed that the variant significantly affected the TRMT61 A protein localization which is thought to impact the mitochondrial and cytosolic functions. CONCLUSION: We reported a novel biallelic variant in TRMT61 A, [NM_152307.3:c.665C > T p.(Ala222Val)], which is associated with autosomal recessive atypical CdLS in a multiplex Rwandan family, the first report from Africa, and the second globally. The study emphasizes the need to expand the availability of ES for molecular characterization of rare diseases for the understudied genetically diverse population of Africa.

Humans↗
PubMed2025

A pathogenic COL7A1 variant highlights semi-dominant inheritance in dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa is a rare subtype of inherited epidermolysis bullosa, caused by variants in the collagen type VII alpha 1 chain (COL7A1) gene (MIM120120). Both autosomal dominant and recessive inheritance has been reported with variable phenotype. We investigated a Pakistani family with dystrophic epidermolysis bullosa via exome sequencing and identified a pathogenic nonsense variant in COL7A1 NM_000094 c.1573 C > T:p.(Arg525*). The inheritance pattern observed was consistent with a semi-dominant model, where heterozygous parents exhibited a mild phenotype, and homozygous children were more severely affected. For dystrophic epidermolysis bullosa, loss-of-function variants are typically associated with the autosomal recessive form, while missense variants are linked to the autosomal dominant form. A review of the literature suggests a semi-dominance pattern for some missense variants, particularly glycine substitutions, but this concept had not been formally recognized. This study highlights the importance of considering semi-dominant inheritance models for dystrophic epidermolysis bullosa and other Mendelian diseases with an autosomal recessive mode of inheritance, as it can significantly impact diagnosis and genetic counseling.

Humans↗
PubMed2025

DNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders.

BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes of BCL11B-related disorders. It is likely that gene-disruptive BCL11B variants and missense variants affecting zinc-binding cysteine and histidine residues cause mild to moderate neurodevelopmental delay with increased propensity for behavioral and dental anomalies, allergies and asthma, and reduced type 2 innate lymphoid cells. Missense variants within C2H2-ZnF DNA-contacting α helices cause highly variable clinical presentations ranging from multisystem anomalies with demise in the first years of life to late-onset, hyperkinetic movement disorder with poor fine motor skills. Those not in direct DNA contact cause a milder phenotype through reduced, target-specific transcriptional activity. However, missense variants affecting C2H2-ZnFs, DNA binding, and "specificity residues" impair BCL11B transcriptional activity in a target-specific, dominant-negative manner along with aberrant regulation of alternative DNA targets, resulting in more severe and unpredictable clinical outcomes. Taken together, we suggest that the phenotypic severity and variability is largely dependent on the DNA-binding affinity and specificity of altered BCL11B proteins.

Adolescent↗
PubMed2024

THBS1 is a new autosomal recessive non-syndromic hearing impairment gene.

BACKGROUND: Prelingual hearing impairment (HI) is genetically highly heterogenous. Early diagnosis and intervention are essential for psychosocial development. In this study we investigated a consanguineous family from Pakistan with autosomal recessive (AR) non-syndromic sensorineural HI (NSHI). METHODS: A DNA sample from an HI member of a consanguineous Pakistani family segregating ARNSHL underwent exome sequencing. Using Sanger sequencing select variants were validated and tested for segregation using DNA samples from additional family members. We further investigated RNA expression data for the candidate gene in mouse and human inner ear and human inner ear organoids using data obtained from the gene Expression Analysis Resource. RESULTS: We identified thrombospondin 1 (THBS1) as a new NSHI gene. A homozygous frameshift variant [c.1470del: p.(Ile491Serfs*45)] was observed in the three hearing-impaired and in the heterozygous state in three unaffected family members. Unlike for most ARNSHI, hearing-impaired individuals had audiograms with a sloping pattern, showing more pronounced HI in the mid and high frequencies (ranging from moderate to profound) compared to the low frequencies. RNA expression data indicates THBS1 is expressed during human inner ear development. Additionally, THBS1 is expressed in the cochlear epithelium and supporting cells of the mouse inner ear during embryonic and postnatal stages. Previously, THBS1 was demonstrated to affect hearing in knockout mice by influencing the formation and function of afferent synapses in the inner ear. CONCLUSIONS: Our findings highlight THBS1 as a potential novel candidate gene for human HI characterized by a sloping high-frequency audio profile. This discovery enhances our understanding of the genetic etiology of HI and will aid in advancing molecular diagnosis.

Humans↗
PubMed2006

A new locus for autosomal dominant amelogenesis imperfecta on chromosome 8q24.3.

Amelogenesis imperfecta (AI) is a collective term used to describe phenotypically diverse forms of defective tooth enamel development. AI has been reported to exhibit a variety of inheritance patterns, and several loci have been identified that are associated with AI. We have performed a genome-wide scan in a large Brazilian family segregating an autosomal dominant form of AI and mapped a novel locus to 8q24.3. A maximum multipoint LOD score of 7.5 was obtained at marker D8S2334 (146,101,309 bp). The disease locus lies in a 1.9 cM (2.1 Mb) region according to the Rutgers Combined Linkage-Physical map, between a VNTR marker (at 143,988,705 bp) and the telomere (146,274,826 bp). Ten candidate genes were identified based on gene ontology and microarray-facilitated gene selection using the expression of murine orthologues in dental tissue, and examined for the presence of a mutation. However, no causative mutation was identified.

Amelogenesis Imperfecta↗
PubMed2006

Phenotypic characterization of DFNA24: prelingual progressive sensorineural hearing impairment.

This article describes the hearing impairment (HI) phenotype which segregates in a large multi-generation Swiss-German family with autosomal dominant nonsyndromic HI. The locus segregating within this pedigree is located on chromosome 4q35-qter and is designated as DFNA24. For this pedigree, audiometric data on 25 hearing-impaired family members are available. It was demonstrated that within this kindred the HI is sensorineural, bilateral, prelingual in onset, and progressive throughout life. Age-related typical audiograms depict steeply down-sloping curves, with moderate high-frequency HI at birth, then steady progression to moderate HI in the low frequencies, severe HI at mid-frequencies and profound HI at high frequencies by age 70. Annual threshold deterioration was approximately 0.5 dB/year at 1-2 kHz after correction for presbycusis.

Adolescent↗
PubMed2006

DFNB68, a novel autosomal recessive non-syndromic hearing impairment locus at chromosomal region 19p13.2.

From a large collection of families with autosomal recessive non-syndromic hearing impairment (NSHI) from Pakistan, linkage has been established for two unrelated consanguineous families to 19p13.2. This new locus was assigned the name DFNB68. A 10 cM genome scan and additional fine mapping were carried out using microsatellite marker loci. Linkage was established for both families to DFNB68 with maximum multipoint LOD scores of 4.8 and 4.6. The overlap of the homozygous regions between the two families was bounded by D19S586 and D19S584, which limits the locus interval to 1.9 cM and contains 1.4 Mb. The genes CTL2, KEAP1 and CDKN2D were screened but were negative for functional sequence variants.

Chromosome Mapping↗
PubMed2006

Localization of a novel autosomal recessive nonsyndromic hearing impairment locus DFNB65 to chromosome 20q13.2-q13.32.

Autosomal recessive nonsyndromic hearing impairment (ARNSHI) is the most frequent form of prelingual hereditary hearing loss in humans. Between 75 and 80% of all nonsyndromic deafness is inherited in an autosomal recessive pattern. Using linkage analysis, we have mapped a novel gene responsible for this form of nonsyndromic hearing impairment, DFNB65, in a consanguineous family from the Azad Jammu and Kashmir regions, which border Pakistan and India. A maximum multipoint LOD score of 3.3 was obtained at marker D20S840. The three-unit support interval is contained between markers D20S902 and D20S430, while the region of homozygosity is flanked by markers D20S480 and D20S430. The novel locus maps to a 10.5-cM region on chromosome 20q13.2-q13.32 and corresponds to a physical map distance of 4.3 Mb. DFNB65 represents the first ARNSHI locus to map to chromosome 20.

Adolescent↗
PubMed2006

A distinct autosomal recessive ataxia maps to chromosome 12 in an inbred family from Jordan.

Autosomal recessive ataxias are a heterogeneous group of rare disorders characterized by early onset ataxia associated with neurologic, ophthalmologic or systemic signs. The ataxias associated with myoclonus, epilepsy and progressive neurological degeneration are usually included with the progressive myoclonus epilepsies, one of which is Unverricht-Lundborg disease. We identified four siblings with ataxia, juvenile onset progressive action tremor and atonic seizures from a Jordanian family. The mode of inheritance of this syndrome is autosomal recessive. We performed a genome-wide screen for linkage and fine mapped the region that contains the disease locus. The four affected siblings have ataxia noted at the onset of walking with dysarthria and bulbar features, but no cerebellar hypoplasia on MRI. They all developed a fine tremor that progressed to a coarse action tremor, as well as atonic seizures. Treatment with valproate fully controlled the seizures and improved the tremor, but did not change the course of the ataxia. We mapped the gene responsible for this disorder to the pericentromeric region of chromosome 12. A recently described autosomal recessive variant of Unverricht-Lundborg disease also maps to the same region. We discuss the similarities and differences between our family and the family with the Unverricht-Lundborg disease variant.

Adolescent↗
PubMed2005

Novel sequence variants in the TMIE gene in families with autosomal recessive nonsyndromic hearing impairment.

To date, 37 genes have been identified for nonsyndromic hearing impairment (NSHI). Identifying the functional sequence variants within these genes and knowing their population-specific frequencies is of public health value, in particular for genetic screening for NSHI. To determine putatively functional sequence variants in the transmembrane inner ear (TMIE) gene in Pakistani and Jordanian families with autosomal recessive (AR) NSHI, four Jordanian and 168 Pakistani families with ARNSHI that is not due to GJB2 (CX26) were submitted to a genome scan. Two-point and multipoint parametric linkage analyses were performed, and families with logarithmic odds (LOD) scores of 1.0 or greater within the TMIE region underwent further DNA sequencing. The evolutionary conservation and location in predicted protein domains of amino acid residues where sequence variants occurred were studied to elucidate the possible effects of these sequence variants on function. Of seven families that were screened for TMIE, putatively functional sequence variants were found to segregate with hearing impairment in four families but were not seen in not less than 110 ethnically matched control chromosomes. The previously reported c.241C>T (p.R81C) variant was observed in two Pakistani families. Two novel variants, c.92A>G (p.E31G) and the splice site mutation c.212 -2A>C, were identified in one Pakistani and one Jordanian family, respectively. The c.92A>G (p.E31G) variant occurred at a residue that is conserved in the mouse and is predicted to be extracellular. Conservation and potential functionality of previously published mutations were also examined. The prevalence of functional TMIE variants in Pakistani families is 1.7% [95% confidence interval (CI) 0.3-4.8]. Further studies on the spectrum, prevalence rates, and functional effect of sequence variants in the TMIE gene in other populations should demonstrate the true importance of this gene as a cause of hearing impairment.

Connexin 26↗
PubMed2005

Localization of a novel locus for alopecia with mental retardation syndrome to chromosome 3q26.33-q27.3.

Alopecia with mental retardation syndrome is a rare autosomal recessive disorder characterized clinically by total or partial alopecia and mental retardation. In an effort to understand the molecular bases of this form of alopecia syndrome, large Pakistani consanguineous kindred with multiple affected individuals has been ascertained from a remote region in Pakistan. Genome wide scan mapped the disease locus on chromosome 3q26.33-q27.3. A maximum two-point LOD score of 3.05 (theta = 0.0) was obtained at marker D3S3583. Maximum multipoint LOD score exceeding 5.0, obtained with several markers, supported the linkage. Recombination events observed in affected individuals localized the disease locus between markers D3S1232 and D3S2436, spanning 11.49-cM region on chromosome 3q26.33-q27.3. Sequence analysis of a candidate gene ETS variant gene 5 from DNA samples of two affected individuals of the family revealed no mutation.

Alopecia↗
PubMed2005

A novel autosomal recessive non-syndromic hearing impairment locus (DFNB47) maps to chromosome 2p25.1-p24.3.

Hereditary hearing impairment (HI) displays extensive genetic heterogeneity. Autosomal recessive (AR) forms of prelingual HI account for approximately 75% of cases with a genetic etiology. A novel AR non-syndromic HI locus (DFNB47) was mapped to chromosome 2p25.1-p24.3, in two distantly related Pakistani kindreds. Genome scan and fine mapping were carried out using microsatellite markers. Multipoint linkage analysis resulted in a maximum LOD score of 4.7 at markers D2S1400 and D2S262. The three-unit support interval was bounded by D2S330 and D2S131. The region of homozygosity was found within the three-unit support interval and flanked by markers D2S2952 and D2S131, which corresponds to 13.2 cM according to the Rutgers combined linkage-physical map. This region contains 5.3 Mb according to the sequence-based physical map. Three candidate genes, KCNF1, ID2 and ATP6V1C2 were sequenced, and were found to be negative for functional sequence variants.

Chromosome Mapping↗
PubMed2005

SimPed: a simulation program to generate haplotype and genotype data for pedigree structures.

With the widespread availability of SNP genotype data, there is great interest in analyzing pedigree haplotype data. Intermarker linkage disequilibrium for microsatellite markers is usually low due to their physical distance; however, for dense maps of SNP markers, there can be strong linkage disequilibrium between marker loci. Linkage analysis (parametric and nonparametric) and family-based association studies are currently being carried out using dense maps of SNP marker loci. Monte Carlo methods are often used for both linkage and association studies; however, to date there are no programs available which can generate haplotype and/or genotype data consisting of a large number of loci for pedigree structures. SimPed is a program that quickly generates haplotype and/or genotype data for pedigrees of virtually any size and complexity. Marker data either in linkage disequilibrium or equilibrium can be generated for greater than 20,000 diallelic or multiallelic marker loci. Haplotypes and/or genotypes are generated for pedigree structures using specified genetic map distances and haplotype and/or allele frequencies. The simulated data generated by SimPed is useful for a variety of purposes, including evaluating methods that estimate haplotype frequencies for pedigree data, evaluating type I error due to intermarker linkage disequilibrium and estimating empirical p values for linkage and family-based association studies.

Computer Simulation↗
PubMed2005

Positive selection of a pre-expansion CAG repeat of the human SCA2 gene.

A region of approximately one megabase of human Chromosome 12 shows extensive linkage disequilibrium in Utah residents with ancestry from northern and western Europe. This strikingly large linkage disequilibrium block was analyzed with statistical and experimental methods to determine whether natural selection could be implicated in shaping the current genome structure. Extended Haplotype Homozygosity and Relative Extended Haplotype Homozygosity analyses on this region mapped a core region of the strongest conserved haplotype to the exon 1 of the Spinocerebellar ataxia type 2 gene (SCA2). Direct DNA sequencing of this region of the SCA2 gene revealed a significant association between a pre-expanded allele [(CAG)8CAA(CAG)4CAA(CAG)8] of CAG repeats within exon 1 and the selected haplotype of the SCA2 gene. A significantly negative Tajima's D value (-2.20, p < 0.01) on this site consistently suggested selection on the CAG repeat. This region was also investigated in the three other populations, none of which showed signs of selection. These results suggest that a recent positive selection of the pre-expansion SCA2 CAG repeat has occurred in Utah residents with European ancestry.

Ataxins↗
PubMed2005

High prevalence of glucose-6-phosphate dehydrogenase deficiency without gene mutation suggests a novel genetic mechanism predisposing to ketosis-prone diabetes.

CONTEXT: Ketosis-prone diabetes (KPD) is mostly observed in males of West African descent and is characterized by phasic or permanent insulin dependence without apparent autoimmune process. OBJECTIVE: KPD subjects display a propensity to hyperglycemia-induced acute insulin deficiency, suggesting that they exhibit a propensity to oxidative stress in beta-cells. The enzyme glucose-6-phosphate dehydrogenase (G6PD) is a defense mechanism against oxidative stress, and G6PD deficiency, an X-linked genetic disorder with male predominance, is frequent in West Africans. We hypothesized that mutations in the G6PD gene could predispose to KPD. DESIGN: We studied G6PD erythrocyte enzyme activity and the insulin secretory reserve (glucagon-stimulated C peptide) in a cohort of hospitalized West Africans with KPD (n = 59) or type 2 diabetes (T2DM; n = 59) and in normoglycemic controls (n = 55). We also studied the G6PD gene in an extended population of KPD patients (n = 100), T2DM patients (n = 59), and controls (n = 85). RESULTS: The prevalence of G6PD deficiency was higher in KPD than in T2DM and controls (42.3%; 16.9%; 16.4%; P = 0.01). In KPD, but not in T2DM, insulin deficiency was proportional to the decreased G6PD activity (r = 0.33; P = 0.04). We found no increase in the prevalence of G6PD gene mutations in KPD compared with T2DM and controls. Rather, we found a 20.3% prevalence of G6PD deficiency in KPD without gene mutation. CONCLUSIONS: This study suggests that 1) G6PD deficiency alone is not causative of KPD; and 2) alterations in genes controlling both insulin secretion and G6PD-mediated antioxidant defenses may contribute to the predisposition to KPD in West Africans.

Africa, Western↗
PubMed2005

Inheritance analysis of congenital left ventricular outflow tract obstruction malformations: Segregation, multiplex relative risk, and heritability.

The left ventricular outflow tract (LVOTO) malformations, aortic valve stenosis (AVS), coarctation of the aorta (COA), and hypoplastic left heart (HLH) constitute a mechanistically defined subgroup of congenital heart defects that have substantial evidence for a genetic component. Evidence from echocardiography studies has shown that bicuspid aortic valve (BAV) is found frequently in relatives of children with LVOTO defects. However, formal inheritance analysis has not been performed. We ascertained 124 families by an index case with AVS, COA, or HLH. A total of 413 relatives were enrolled in the study, of which 351 had detailed echocardiography exams for structural heart defects and measurements of a variety of aortic arch, left ventricle, and valve structures. LVOTO malformations were noted in 30 relatives (18 BAV, 5 HLH, 3 COA, and 3 AVS), along with significant congenital heart defects (CHD) in 2 others (32/413; 7.7%). Relative risk for first-degree relatives in this group was 36.9, with a heritability of 0.71-0.90. Formal segregation analysis suggests that one or more minor loci with rare dominant alleles may be operative in a subset of families. Multiplex relative risk analysis, which estimates number of loci, had the highest maximum likelihood score in a model with 2 loci (range of 1-6 in the lod-1 support interval). Heritability of several aortic arch measurements and aortic valve was significant. These data support a complex but most likely oligogenic pattern of inheritance. A combination of linkage and association study designs is likely to enable LVOTO risk gene identification. This data can also provide families with important information for screening asymptomatic relatives for potentially harmful cardiac defects.

Analysis of Variance↗
PubMed2005

A novel autosomal recessive nonsyndromic hearing impairment locus (DFNB42) maps to chromosome 3q13.31-q22.3.

A consanguineous family with autosomal recessive nonsyndromic hearing impairment (NSHI) was ascertained in Pakistan and displayed significant evidence of linkage to 3q13.31-q22.3. The novel locus (DFNB42) segregating in this kindred, maps to a 21.6 cM region according to a genetic map constructed using data from both the deCode and Marshfield genetic maps. This region of homozygosity is flanked by markers D3S1278 and D3S2453. A maximum multipoint LOD score of 3.72 was obtained at marker D3S4523. DFNB42 represents the third autosomal recessive NSHI locus to map to chromosome 3.

Audiometry↗