Spinocerebellar ataxia type 10 and Huntington disease-like 2 in Venezuela: Further evidence of two different ancestral founder effects.

INTRODUCTION: The American continent populations have a wide genetic diversity, as a product of the admixture of three ethnic groups: Amerindian, European, and African Sub-Saharan. Spinocerebellar ataxia type 10 (SCA10) and Huntington disease-like 2 (HDL2) have very ancient ancestral origins but are restricted to two populations: Amerindian and African Sub-Saharan, respectively. This study aimed to investigate the genetic epidemiological features of these diseases in Venezuela. METHODS: In-phase haplotypes with the expanded alleles were established in seven unrelated index cases diagnosed with SCA10 and in 11 unrelated index cases diagnosed with HDL2. The origins of remote ancestors were recorded. RESULTS: The geographic origin of the ancestors showed grouping in clusters. SCA10 had a minimal general prevalence of 1:256,174 families in the country, but within the identified geographic clusters, the prevalence ranged from 5 per 100,000 to 43 per 100,000 families. HDL2 had a general prevalence of 1:163,016 families, however, within the clusters, the prevalence ranged from 31 per 100,000 to 60 per 100,000 families. The locus-specific haplotype shared by all families worldwide, including the Venezuelans, supports a single old ancestral origin in each case. CONCLUSION: Knowing the genetic ancestry and geographic origins of patients in Ibero-American mixed populations could have significant diagnostic implications; thus, both diseases in Venezuela should always be first explored in patients with a suggestive phenotype and ancestors coming from the same known geographic clusters.

Fragile X syndrome in the largest world clustering. I. Genetic epidemiology and founder effect outline.

The FMR1 5' regulation gene region harbors a CGG trinucleotide repeat expansion (CGG-TRE) that causes Fragile X syndrome (FXS) when it expands to more than 200 repetitions. Ricaurte is a small village in southwestern Colombia, with an FXS prevalence of 1 in 38 men and 1 in 100 women (~100 times higher than the worldwide reported prevalence), defining Ricaurte as the largest FXS cluster in the world. In the present study, using next-generation sequencing of whole exome capture, we genotype 55 individuals from Ricaurte (49 with either full mutation or with premutation), four individuals from neighboring villages (with either the full mutation or with the premutation), and one unaffected woman, native of Ricaurte, who did not belong to any of the affected families. With advanced clustering and haplotype reconstruction, we modeled a common haplotype of 33 SNPs spanning 83,567,899 bp and harboring the FMR1 gene. This reconstructed haplotype was found in all the men from Ricaurte who carried the expansion, demonstrating that the genetic conglomerate of FXS in this population is due to a founder effect. The definition of this founder effect and its population outlining will allow a better prediction, follow-up, precise and personalized characterization of epidemiological parameters, better knowledge of the disease's natural history, and confident improvement of the clinical attention, life quality, and health interventions for this community.

Genotype and Phenotype Characterization of Patients with Mucopolysaccharidosis IV-A in Chile.

Introduction: Morquio syndrome or mucopolysaccharidosis type IV-A (MPS IV-A) is an autosomal recessive disease caused by biallelic variants in the GALNS gene, encoding the lysosomal enzyme GalN6S, responsible for glycosaminoglycan keratan sulfate and chondroitin-6-sulfate degradation. Studies have shown that the degree of evolutionary and chemical divergence of missense variants in GalN6S when compared to ancestral amino acids is associated with the severity of the syndrome, suggesting a genotype-phenotype correlation. There is little information on Latin American patients with MPS IV-A that replicate these findings. This study aimed to characterize the phenotype and genotype from patients with MPS IV-A, who are under Enzyme Replacement Therapy at the Children's Neuropsychiatry Service of the Hospital Clínico San Borja Arriarán, Santiago, Chile, and to determine if there is any association between genotype and phenotype with those findings. Methods: Information was collected from medical charts, all patients went through a GalN6S enzymatic activity measurement in leukocytes from peripheral blood, and the GALNS gene was sequenced for all cases. Results: 12 patients with MPS IV-A were recruited, all patients presented multisystem involvement, mostly skeletal, and 75% of cases underwent surgical interventions, and cervical arthrodesis was the most frequent procedure. In regards of the genotype, the two most frequent variants were c.319+2T>C (n = 10, 41.66%) and p.(Arg386Cys) (n = 8, 33.33%), the first one was previously described in 2018 in a patient from Chile [Bochernitsan et al., 2018]. Conclusion: This is the first time that a genotype-phenotype correlation has been studied by analyzing the variants effect on the molecular structure of human GalN6S and the evolutionary conservation degree of affected residues in a cohort of patients in Chile. Albeit our work could not find statistically significant associations, we may infer that the evolutionary conservations of affected amino acids and the effect of variants on enzyme structure may play a main role. Further analyzes should consider a meta-analysis of published cases with genotype data and larger samples and include other variables that could provide more information. Finally, our data strongly suggest that variant c.319+2T>C could have a founder effect in Chilean patients with MPS IV-A.

The Second Highest Prevalence of Celiac Disease Worldwide: Genetic and Metabolic Insights in Southern Brazilian Mennonites.

Celiac disease (CD), despite its high morbidity, is an often-underdiagnosed autoimmune enteropathy. Using a modified version of the Brazilian questionnaire of the 2013 National Health Survey, we interviewed 604 Mennonites of Frisian/Flemish origin that have been isolated for 25 generations. A subgroup of 576 participants were screened for IgA autoantibodies in serum, and 391 participants were screened for HLA-DQ2.5/DQ8 subtypes. CD seroprevalence was 1:29 (3.48%, 95% CI = 2.16-5.27%) and biopsy-confirmed CD was 1:75 (1.32%, 95% CI = 0.57-2.59%), which is superior to the highest reported global prevalence (1:100). Half (10/21) of the patients did not suspect the disease. HLA-DQ2.5/DQ8 increased CD susceptibility (OR = 12.13 [95% CI = 1.56-94.20], p = 0.003). The HLA-DQ2.5 carrier frequency was higher in Mennonites than in Brazilians (p = 7 × 10-6). HLA-DQ8 but not HLA-DQ2.5 carrier frequency differed among settlements (p = 0.007) and was higher than in Belgians, a Mennonite ancestral population (p = 1.8 × 10-6), and higher than in Euro-Brazilians (p = 6.5 × 10-6). The glutathione pathway, which prevents reactive oxygen species-causing bowel damage, was altered within the metabolic profiles of untreated CD patients. Those with lower serological positivity clustered with controls presenting close relatives with CD or rheumatoid arthritis. In conclusion, Mennonites have a high CD prevalence with a strong genetic component and altered glutathione metabolism that calls for urgent action to alleviate the burden of comorbidities due to late diagnosis.

Biallelic variants in DNA2 cause poikiloderma with congenital cataracts and severe growth failure reminiscent of Rothmund-Thomson syndrome.

Rothmund-Thomson syndrome (RTS) is a rare, heterogeneous autosomal recessive genodermatosis, with poikiloderma as its hallmark. It is classified into two types: type I, with biallelic variants in ANAPC1 and juvenile cataracts, and type II, with biallelic variants in RECQL4, increased cancer risk and no cataracts. We report on six Brazilian probands and two siblings of Swiss/Portuguese ancestry presenting with severe short stature, widespread poikiloderma and congenital ocular anomalies. Genomic and functional analysis revealed compound heterozygosis for a deep intronic splicing variant in trans with loss of function variants in DNA2, with reduction of the protein levels and impaired DNA double-strand break repair. The intronic variant is shared by all patients, as well as the Portuguese father of the European siblings, indicating a probable founder effect. Biallelic variants in DNA2 were previously associated with microcephalic osteodysplastic primordial dwarfism. Although the individuals reported here present a similar growth pattern, the presence of poikiloderma and ocular anomalies is unique. Thus, we have broadened the phenotypical spectrum of DNA2 mutations, incorporating clinical characteristics of RTS. Although a clear genotype-phenotype correlation cannot be definitively established at this moment, we speculate that the residual activity of the splicing variant allele could be responsible for the distinct manifestations of DNA2-related syndromes.

Evidence for a Founder Effect of SDHB Exon 1 Deletion in Brazilian Patients With Paraganglioma.

CONTEXT: Limited information is available concerning the genetic spectrum of pheochromocytoma and paraganglioma (PPGL) patients in South America. Germline SDHB large deletions are very rare worldwide, but most of the individuals harboring the SDHB exon 1 deletion originated from the Iberian Peninsula. OBJECTIVE: Our aim was to investigate the spectrum of SDHB genetic defects in a large cohort of Brazilian patients with PPGLs. METHODS: Genetic investigation of 155 index PPGL patients was performed by Sanger DNA sequencing, multiplex ligation-dependent probe amplification, and/or target next-generation sequencing panel. Common ancestrality was investigated by microsatellite genotyping with haplotype reconstruction, and analysis of deletion breakpoint. RESULTS: Among 155 index patients, heterozygous germline SDHB pathogenic or likely pathogenic variants were identified in 22 cases (14.2%). The heterozygous SDHB exon 1 complete deletion was the most frequent genetic defect in SDHB, identified in 8 out of 22 (36%) of patients. Haplotype analysis of 5 SDHB flanking microsatellite markers demonstrated a significant difference in haplotype frequencies in a case-control permutation test (P = 0.03). More precisely, 3 closer/informative microsatellites were shared by 6 out of 8 apparently unrelated cases (75%) (SDHB-GATA29A05-D1S2826-D1S2644 | SDHB-186-130-213), which was observed in only 1 chromosome (1/42) without SDHB exon 1 deletion (X2 = 29.43; P < 0.001). Moreover, all cases with SDHB exon 1 deletion had the same gene breakpoint pattern of a 15 678 bp deletion previously described in the Iberian Peninsula, indicating a common origin. CONCLUSION: The germline heterozygous SDHB exon 1 deletion was the most frequent genetic defect in the Brazilian PPGL cohort. Our findings demonstrated a founder effect for the SDHB exon 1 deletion in Brazilian patients with paragangliomas.

PSEN1 c.1292C<A Variant and Early-Onset Alzheimer's Disease: A Scoping Review.

Alzheimer's disease (AD) is the most common cause of dementia, characterized by progressive loss of cognitive function, with ß-amyloid plaques and neurofibrillary tangles being its major pathological findings. Although the disease mainly affects the elderly, c. 5-10% of the cases are due to PSEN1, PSEN2, and APP mutations, principally associated with an early onset of the disease. The A413E (rs63750083) PSEN1 variant, identified in 2001, is associated with early-onset Alzheimer's disease (EOAD). Although there is scant knowledge about the disease's clinical manifestations and particular features, significant clinical heterogeneity was reported, with a high incidence of spastic paraparesis (SP), language impairments, and psychiatric and motor manifestations. This scoping review aims to synthesize findings related to the A431E variant of PSEN1. In the search, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and the guidelines proposed by Arksey and O'Malley. We searched and identified 247 studies including the A431E variant of PSEN1 from 2001 to 2021 in five databases and one search engine. After the removal of duplicates, and apply inclusion criteria, 42 studies were finally included. We considered a narrative synthesis with a qualitative approach for the analysis of the data. Given the study sample conformation, we divided the results into those carried out only with participants carrying A431E (seven studies), subjects with PSEN variants (11 studies), and variants associated with EOAD in PSEN1, PSEN2, and APP (24 studies). The resulting synthesis indicates most studies involve Mexican and Mexican-American participants in preclinical stages. The articles analyzed included carrier characteristics in categories such as genetics, clinical, imaging techniques, neuropsychology, neuropathology, and biomarkers. Some studies also considered family members' beliefs and caregivers' experiences. Heterogeneity in both the studies found and carrier samples of EOAD-related gene variants does not allow for the generalization of the findings. Future research should focus on reporting data on the progression of carrier characteristics through time and reporting results independently or comparing them across variants.

Recent Differentiation of Aquatic Bacterial Communities in a Hydrological System in the Cuatro Ciénegas Basin, After a Natural Perturbation.

Pozas Rojas is a hydrological system comprising nine isolated shallow ponds and a deep lagoon, which were temporally merged in 2010 by increased rainfall due to a tropical cyclone. In this work, we assess which components, biotic interactions, or environment filtering effects, drive the assembly of microbial communities after a natural perturbation. Arsenic, pH, and temperature are among the most significant environmental variables between each pond, clustering the samples in two main groups, whereas microbial composition is diverse and unique to each site, with no core at the operational taxonomic unit level and only 150 core genera when studied at the genus level. Los Hundidos lagoon has the most differentiated community, which is highly similar to the epipelagic Mediterranean Sea communities. On the other hand, the shallow ponds at the Pozas Rojas system resemble more to epicontinental hydrological systems, such as some cold rivers of the world and the phreatic mantle from Iowa. Overall, despite being a sole of water body 2 years prior to the sampling, interspecific interactions, rather than environmental selection, seem to play a more important role in Pozas Rojas, bolstered by founder effects on each poza and subsequent isolation of each water body.

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects.

BACKGROUND: The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. METHODS: We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer's disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. RESULTS: We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. CONCLUSIONS: Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.

HINT1 founder mutation causing axonal neuropathy with neuromyotonia in South America: A case report.

BACKGROUND: Recessive loss-of-function mutations in HINT1 are associated with predominantly motor axonal peripheral neuropathy with neuromyotonia. Twenty-four distinct pathogenic variants are reported all over the world, including four confirmed founder variations in Europe and Asia. The majority of patients carry the ancient Slavic founder variant c.110G>C (p.Arg37Pro) that shows a distribution gradient from east to west throughout Europe. METHODS: We report a case of HINT1 neuropathy in South America, identified by massive parallel sequencing of a neuropathy gene panel. To investigate the origin of the variant, we performed haplotyping analysis. RESULTS: A Brazilian adolescent presented with recessive axonal motor neuropathy with asymmetric onset and fasciculations. Neuromyotonia was found on needle electromyography. His parents were not consanguineous and had no European ancestry. The patient carried biallelic pathogenic p.Arg37Pro alterations in the first exon of HINT1. Both alleles were identical by descent and originated from the same ancestral founder allele as reported in Europe. CONCLUSION: Our findings expand the geographic distribution of HINT1 neuropathy to South America, where we describe a recognized founder variant in a Brazilian adolescent with no apparent European ancestry. We confirm the association of the hallmark sign of neuromyotonia with the disease.

Demographic, clinical, and ancestry characterization of a large cluster of mucopolysaccharidosis IV A in the Brazilian Northeast region.

Mucopolysaccharidosis (MPS) IVA is a rare autosomal recessive disease with a highly variable distribution worldwide. Discrepancies in the incidence of MPS IVA among populations of different ethnicities are mostly attributed to founder effects. Demographic and clinical data from 28 MPS IVA patients, followed at a single center, and ancestry (Y chromosome and mitochondrial markers) of a subsample of 17 patients, most with the p.Ser341Arg (c.1023C>G) mutation were analyzed. Parental consanguinity was observed in 15/20 couples; a rare homozygous N-acetylgalactosamine-6-sulfatase (GALNS) mutation was found in 7/16 families with intra-familial phenotypic heterogeneity. Paternal ancestry was 94.2% (16/17) European, 5.8% (1/17) African, and 0% Amerindian. The European paternal haplogroups R1a, R1b, and R* accounted for 94.2% (16/17) of the patients. The R1b haplogroup, identified in 59% (10/17) of the patients, is frequently found in populations from the Iberian Peninsula. European, Amerindian, and African maternal ancestry was observed in 46.9% (8/17), 35.4% (6/17), and 17.7% (3/17) of the patients, respectively. Study of a cluster of MPS IVA patients from Northeastern Brazil, with high parental consanguinity and phenotypic heterogeneity showed predominantly European parental ancestry. This ancestry finding corroborates historical data on the local settlement, formed predominantly by European men.

La endogamia como causa de consanguinidad y su asociación con anomalías congénitas / Endogamy as a cause of consanguinity and its association with congenital anomalies

El papel de la endogamia como causa de homocigosidad en la salud humana es un foco de interés en genética médica, debido a su relación con anomalías congénitas y patologías genéticas recesivas. Es un tema importante a pesar de que las tasas de uniones consanguíneas en ciertas sociedades han disminuido con el tiempo; sin embargo, en algunas comunidades se han mantenido estables o han aumentado. La consanguinidad es practicada hasta en el 10% de la población mundial, y los motivos más comúnmente citados son socioculturales y socioeconómicos. Aunque se ha visto una disminución de esta práctica, probablemente por la migración urbana y el aumento de las tasas de educación, la consanguinidad continúa practicándose en todo el mundo. Los efectos más significativos sobre los resultados reproductivos se deben, principalmente, a condiciones hereditarias autosómicas recesivas, que también aumentan la frecuencia de algunos desórdenes médicos. El objetivo de esta revisión es dar a conocer la epidemiología y los factores predisponentes de la consanguinidad, así como presentar la evidencia actual de la asociación entre la consanguinidad originada en la endogamia y las anormalidades congénitas y patologías médicas como consecuencia de trastornos genéticos mendelianos. Se requiere un enfoque culturalmente apropiado para el asesoramiento genético en relación con la endogamia

The role of consanguinity as a cause of homozygosity in human health is a focus of interest in medical genetics, due to its relationship with congenital anomalies and recessive genetic pathologies. This is an important issue since the rates of consanguineous unions in certain societies have decreased over time, but have remained stable or have increased in others. Consanguinity is practiced in up to 10% of the world population, and the most common reasons are sociocultural and socioeconomic factors. Although there has been a decrease in this practice, probably due to urban migration and an increase in education rates, consanguinity continues to be practiced throughout the world. The most significant effects on reproductive outcomes are mainly due to autosomal recessive hereditary conditions, that also increase the frequency of medical disorders. The aim of this review is to present the current evidence of the association between consanguinity originating from endogamy, with congenital abnormalities and medical disorders originated from mendelian genetic pathologies. A cultural appropriate approach is required for genetic counseling in relation to consanguineous endogamy

New mutation associated with autosomal dominant polycystic kidney disease with founder effect located in the alpujarra region of granada. / Nueva mutación asociada a poliquistosis renal autosómica dominante con efecto fundador localizada en la Alpujarra de Granada.

OBJECTIVE: To demonstrate that the variant not described in PKD1 gene c.7292T> A, identified in four families from the Alpujarra in Granada, is the cause of autosomal dominant polycystic kidney disease (ADPKD). This variant consists of a transversion of thymine (T) by adenine (A) that at the level of the Polycystin 1 protein produces a change of leucine (Leu / L) by Glutamine (Gln / Q) in position 2431 (p.Leu2431Gln). METHOD: Sociodemographic and clinical variables were registered using clinical histories, genealogical trees, ultrasounds and genetic analysis to ADPKD and healthy individuals belonging to these families in the context of segregation study. RESULTS: All PKD individuals carried the c.7292T>A variant in heterozygosis, whereas healthy ones did not. Among all ADPKD patients, 62.9% were women. ADPKD diagnosis was made at 29.3 ± 15.82 years, after having the first child in 64.8%. The main reasons for diagnosis were family history and hematuria episodes. The onset of renal replacement therapy (RRT) occurred at 55.8 ± 7.62 years (range 44-67), and death at 63 ± 92.2 years (range 48-76), being the cause unknown, cardiovascular and insufficiency kidney the most frequent; the median of renal survival was established at 58.5 ± 0.77 years and the median survival of patients at 67.2 ± 3.54 years. No differences in kidney and patient survivals were observed according to sex. Among deceased patients, 52.2% required RRT and 94.4% suffered from renal failure. CONCLUSIONS: The variant c.7292T>A in PKD1 gene is responsible for the disease, and its distribution in the Alpujarra region of Granada suggests a founder effect. In ADPKD it is necessary to perform segregation studies that help us to reclassify genetic variants, in this case from indeterminate to pathogenic.

Non-dystrophic myotonia Chilean cohort with predominance of the SCN4A Gly1306Glu variant.

Non-dystrophic myotonias are a group of rare neuromuscular diseases linked to SCN4A or CLCN1. Among the subtypes, myotonia permanens, associated with the Gly1306Glu variant of SCN4A, is a relatively less frequent but more severe form. Most reports of non-dystrophic myotonias describe European populations. Therefore, to expand the genetic and phenotypic spectrum of this disorder, we evaluated 30 Chilean patients with non-dystrophic myotonias for associated variants and clinical characteristics. SCN4A variants were observed in 28 (93%) of patients, including 25 (83%) with myotonia permanens due to the Gly1306Glu variant. Myotonia permanens was inherited in 24 (96%) patients; the mean age of onset was 6 months, and the initial symptoms were orbicularis oculi myotonia in 17 (74%) patients and larynx myotonia in 12 (52%) patients. The extraocular muscles were involved in 11 (44%) patients, upper limbs in 20 (80%), and lower limbs in 21 (84%). Thirteen (52%) patients experienced recurrent pain and 10 (40%) patients reported limitations in daily life activities. Carbamazepine reduced myotonia in eight treated patients. The high frequency of the Gly1306Glu variant in SCN4A in Chilean patients suggests a founder effect and expands its phenotypic spectrum.

LDLR Gene Mutation p.Asp360His and Familial Hypercholesterolemia in a Mexican Community.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by an increased LDL-cholesterol (LDLc) serum concentration and premature cardiovascular disease. Screening of small populations where at least one homozygous (HoFH) patient has been identified may be a proper approach for detecting FH patients. Previously, we reported an HoFH patient carrying the mutation p.Asp360His LDLR, who was born in the Mexican community El Triunfo (Quimixtlan, Puebla). AIM OF THE STUDY: To identify patients with familial hypercholesterolemia in the community El Triunfo and to describe their clinical and biochemical characteristics. METHODS: We studied 308 individuals by quantifying lipid levels and by DNA sequencing. RESULTS: Sixteen of 308 individuals presented an LDLc level >170 mg/dL and all of them turned out to be heterozygous for the LDLR p.Asp360His variant. Subsequently, 34 of their first-degree relatives (mainly siblings and parents) were genotyped rendering six additional HeFH patients, which resulted in 22 carriers of the mutated allele. The study of six LDLR polymorphisms in four unrelated individuals from the community (one HoFH and three HeFH) showed the same haplotype combination, suggesting a unique ancestral origin of the mutation. CONCLUSIONS: The community El Triunfo, has the highest worldwide frequency ever reported of HeFH, with 7.14% (22/308, equivalent to 1/14 inhabitants). Since the HeFH patients showed variable biochemical expression, we suggest looking for factors with the potential to modify the phenotype. Finally, we stress the importance of establishing accurate LDLc cut-off points applicable to Mexican population for the diagnosis of FH.

Genetic variants linked to folliculogenesis and successful pregnancy are not associated with twin births in a twins' town.

Background: Cândido Godói (CG) is a small city in South Brazil in which natural twin births (both monozygotic and dizygotic) occur at an unusually high rate and the twin trait runs through the local families, which are mostly European descendants. We have argued that a genetic founder effect must have occurred during the settlement of CG and that genetic factors may help to explain the familial aggregation of twinning in that city.Objective: The aim of this study was to evaluate single nucleotide polymorphisms (SNPs) related to folliculogenesis (rs6166:C > T in FSHR, rs11031006:G > A near FSHB, and rs17293443:T > C in SMAD3) and successful pregnancies (rs2010963:C > G in VEGFA, rs1800629:G > A in TNF, rs1801131:T > G and rs1801133:G > A in MTHFR) in mothers from CG.Study design: Forty-four mothers of twins (the case group) and 102 mothers of singletons (the control group) from CG were investigated. Genotypes were determined using real-time PCR (TaqMan® SNP Genotyping Assay).Results: For all SNPs, the distributions of the genotypic and allelic frequencies were similar between cases and controls. Interestingly, a deviation from the Hardy-Weinberg equilibrium was detected for SNP rs11031006:G > A near FSHB in the control population. Different combinations of risk alleles and haplotypic analyses were homogeneously distributed between cases and controls.Conclusion: These results suggest a lack of association between the seven studied SNPs and twin births in CG. However, we hypothesized that other genetic variants related to folliculogenesis or successful pregnancies may be involved in this phenomenon. Identifying such genetic components may be important not only for the Brazilian "Twins' Town" but also for a better understanding of twinning in general.

5α-Reductase type 2 deficiency in families from an isolated Andean population in Venezuela.

5α-Reductase type 2 deficiency causes a 46,XY disorder of sex development (DSD) characterized by ambiguous external genitalia, rudimentary prostate, and normal internal genitalia. The disease prevalence worldwide is low, but in a small and isolated village of the Venezuelan Andes, a higher incidence has been found. DNA analysis of the SRD5A2 gene was performed in three inbred affected individuals clinically diagnosed with DSD. The entire coding regions, the p.L89V polymorphism (rs523349) and five intragenic SNPs (rs2300702, rs2268797, rs2268796, rs4952220, rs12470196) used to construct haplotypes were analyzed by Sanger sequencing. To assess the probable ethnic origin of the mutation in this geographic isolate, a population structure analysis was performed. Homozygosis for the p.N193S mutation was found in all patients, with a mutation carrier frequency of 1:80 chromosomes (0.0125) in the geographic focus, suggesting a founder phenomenon. The results of the population structure analysis suggested a mutation origin closer to the Spanish populations, according to the clusters grouping. The genotype-phenotype correlation in the patients was not absolute, being hypospadias and cryptorchidism the main traits that differentiate affected individuals.

Historical Migration revealed through a Case of Autosomal Dominant Alzheimer's Disease.

With the increasing geopolitical instability and environmental devastation occurring across the globe, human migration is increasing. We report a case that illustrates a migration pattern seen a century ago that is currently in the process of repeating itself. Using information from a neuropathological examination, genetic analyses, and historical sources, we linked a patient with autosomal dominant Alzheimer's disease in Hawai'i with her ancestors in Puerto Rico. In this patient we identified the G206A PSEN1 mutation, previously identified as being linked to a founder effect from Puerto Rico. At the turn of the twentieth century, due to devastating hurricanes in Puerto Rico and the island's new status as a possession of the United States, over 5,000 Puerto Ricans, including the grandparents of our patient, migrated to Hawai'i. This short-term but historic migration has resulted in a significant population of Puerto Ricans in Hawai'i, today. As physicians we sometimes have the opportunity and privilege, through the patients who come to us for help, to be indirect witnesses to such historical events and movements. These occurrences can inform the present and also portend future developments in this rapidly changing world.

Molecular characterization of a large group of Mucopolysaccharidosis type IIIC patients reveals the evolutionary history of the disease.

Mucopolysaccharidosis type IIIC (MPSIIIC) is a severe, rare autosomal recessive disorder caused by variants in the heparan-α-glucosaminide N-acetyltransferase (HGSNAT) gene which result in lysosomal accumulation of heparan sulfate. We analyzed clinical presentation, molecular defects and their haplotype context in 78 (27 novel) MPSIIIC cases from 22 countries, the largest group studied so far. We describe for the first time disease-causing variants in the patients from Brazil, Algeria, Azerbaijan, and Iran, and extend their spectrum within Canada, Colombia, Turkey, and the USA. Six variants are novel: two missense, c.773A>T/p.N258I and c.1267G>T/p.G423W, a nonsense c.164T>A/p.L55*, a splice-site mutation c.494-1G>A/p.[P165_L187delinsQSCYVTQAGVRWHHLGSLQALPPGFTPFSYLSLLSSWNC,P165fs], a deletion c.1348delG/p.(D450fs) and an insertion c.1479dupA/p.(Leu494fs). The missense HGSNAT variants lacked lysosomal targeting, enzymatic activity, and likely the correct folding. The haplotype analysis identified founder mutations, p.N258I, c.525dupT, and p.L55* in the Brazilian state of Paraiba, c.493+1G>A in Eastern Canada/Quebec, p.A489E in the USA, p.R384* in Poland, p.R344C and p.S518F in the Netherlands and suggested that variants c.525dupT, c.372-2G>A, and c.234+1G>A present in cis with c.564-98T>C and c.710C>A rare single-nucleotide polymorphisms, have been introduced by Portuguese settlers in Brazil. Altogether, our results provide insights into the origin, migration roots and founder effects of HGSNAT disease-causing variants, and reveal the evolutionary history of MPSIIIC.

Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr).

INTRODUCTION: A small percentage of Alzheimer's disease (AD) cases are caused by genetic mutations with autosomal dominant inheritance. We report a family with a novel variant in PSEN1. METHODS: We performed clinical and genetic evaluation of 93 related individuals from a Colombian admixed population. 31 individuals had whole-genome sequencing. RESULTS: Genetic analysis revealed a missense variant in PSEN1 (NM_000021.3: c.1247T>C p.Ile416Thr), which originated on an African haplotype and segregated with AD logarithm of the odds score of 6. Their clinical phenotype is similar to sporadic AD except for earlier age at onset: the mean age at onset for mild cognitive impairment was 47.6 years (standard deviation 5.83) and for dementia 51.6 years (standard deviation 5.03). DISCUSSION: Ile416Thr is a novel pathogenic variant that causes AD in the sixth decade of life. The history of the region that included slave importation and admixtures within a confined geographic locale represents a "mini-population bottleneck" and subsequent emergence of a rare dominant mutation.