Consanguineous Cases Research Articles

Routine detection of consanguinity through preimplantation genetic testing in human embryos

Research QuestionCan a single nucleotide polymorphism (SNP)-array-based preimplantation genetic testing (PGT) platform routinely detect consanguinity in preimplantation embryos? DesignA validation set consisting of twenty-nine clinical PGT cases (five cases with confirmed consanguinity (positive control cases) and twenty-four randomly selected nonconsanguineous cases (negative control cases)) was used to define a genetic threshold for routine detection of consanguinity. PLINK software was used to identify all regions of homozygosity (ROH) greater than 5 Mb on each autosome (Purcell et al., 2007). The percentage of ROH was then calculated and compared between the positive and negative control cases to determine a threshold. Next, the threshold was used to create a specific criterion that was applied to 6,380 clinical PGT cases (27,378 total embryos) to calculate the prevalence of consanguineous cases within a single PGT laboratory. ResultsThe selected criterion defined cases as consanguineous when they contained two or more embryos with ROH percentages greater than or equal to 0.5%. Positive and negative control cases from the validation set fulfilled and failed this criterion, respectively. Of the 6,380 cases evaluated, 0.4% (25) were defined as consanguineous. ConclusionsThis study describes a PGT platform that can routinely screen for parental consanguinity by evaluating regions of homozygosity in IVF-derived embryos during routine genetic testing. Consanguinity can be detected without prior knowledge of a parental relationship. This can help to improve the utility of PGT and identify embryos at increased risk of recessive disease associated with consanguinity.

P-540 Strategic implementation of PGT-M for multiple genes post qhole exome sequencing in couples with familial history: a comprehensive study

Abstract Study question What advantages does Whole Exome Sequencing offer to couples with a familial history of hereditary disorders? Summary answer WES offers a comprehensive risk assessment, facilitating the development of an effective PGT-M for Multiple Genes in the prevention of severe diseases in their offspring What is known already PGT-M enables the transfer of unaffected embryos to couples at risk of transmitting monogenic disorders. With the advancements in technologies like Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) identifying causal mutations, there is a growing demand for PGT-M applications that concurrently assess multiple genetic disorders. This is particularly crucial, as families initially referred for one condition may later be discovered to be at risk for additional monogenic disorders due to the common carriership status of the couples. Study design, size, duration This is a retrospective study including couples with previous familial history of genetic disorders referred to a single genetic unit between years 2020-2024. Either WES-DUO or WES-TRIO analysis were performed in the absence or presence of an affected child, respectively. Participants/materials, setting, methods WES-DUO or WES-Trio analyses were performed on 94 couples with a familial history of genetic diseases encompassing diverse medical domains. Around 50% of the couples exhibited consanguinity. Utilizing the Novaseq 6000 next-generation sequencing platform, exonic regions were sequenced with an average coverage of 100X. Bioinformatic analysis followed the manufacturer’s recommended workflow, and variant analysis adhered to ACMG criteria, ClinVar, and HGMD. Segregation analysis was conducted through Sanger sequencing using region-specific primers. Main results and the role of chance WES, followed by segregation analysis, pinpointed reportable pathogenic or likely pathogenic variants in 46 out of 94 families as the root cause of the referral condition. Interestingly, 42 of these families exhibited at least one additional common gene mutation in both partners. Notably, among the 27 families with confirmed diagnoses, in vitro fertilization (IVF) and preimplantation genetic testing for monogenic disorders (PGT-M) were undertaken. Within this cohort, PGT-M for multiple genes was successfully conducted in 22 families, 96 embryos were found to be transferable resulting in the birth of healthy infants. Limitations, reasons for caution The overall diagnostic confirmation rate of WES analysis reached 48.9%. A quite high diagnostic yield achieved in this study is notably influenced by the substantial prevalence of consanguineous cases. Wider implications of the findings This study highlights the need for implementing PGT-M for multiple genes. Failure to undergo such testing would potentially lead to the birth of children affected by other conditions.This study also underscores the efficiency of encompassing WES, mutation confirmation, segregation analysis, bioinformatic processing and PGT applications in a single genetic unit. Trial registration number none

A Rare Consanguineous Case of Alazami Syndrome in a Jordanian Family: Clinical Presentation, Genetic Analysis, and Therapeutic Approaches - A Case Report

Objective: Alazami syndrome (AS) is an infrequent genetic disorder inherited in an autosomal recessive pattern, characterized by the presence of multiple congenital abnormalities. This study explores a case of a 4-year-old girl with AS, examining symptoms, genetic factors, and treatment efficacy. Case report: A 4-year-old girl, born to consanguineous Jordanian parents, displayed dysmorphic features including low birth weight, microcephaly, hyperthyroidism, short stature, blue sclera, triangular-shaped face, deep-set eyes, narrow palpebral fissures, and a prominent forehead. Examination revealed height (92 cm) and weight (7.7 kg) below the 5th and 3rd percentiles respectively. Blood tests and renal ultrasound were normal. Whole exome sequencing (WES) identified a homozygous eight-base pair deletion within exon 5 of the LARP7 gene on chromosome 4q25, confirming the diagnosis of AS, an autosomal recessive disorder. This variant induces frameshift mutations leading to premature stop codons, suggesting a probable mechanism of illness via loss of function. Treatment involving growth monitoring and therapy led to significant improvements in height, weight, and communication skills within three months. Conclusion: We describe a rare autosomal recessive AS case due to consanguinity, with a frameshift mutation in the LARP7 gene found via WES. Our AS treatment program effectively alleviates symptoms and enhances developmental progress.

Expanding Access to Noninvasive Prenatal Diagnosis for Monogenic Conditions to Consanguineous Families.

Cell-free fetal DNA exists within the maternal bloodstream during pregnancy and provides a means for noninvasive prenatal diagnosis (NIPD). Our accredited clinical service offers definitive NIPD for several autosomal recessive (AR) and X-linked conditions using relative haplotype dosage analysis (RHDO). RHDO involves next-generation sequencing (NGS) of thousands of common single nucleotide polymorphism (SNPs) surrounding the gene of interest in the parents and an affected or unaffected offspring to conduct haplotype phasing of the high- and low-risk alleles. NGS is carried out in parallel on the maternal cell-free DNA, and fetal inheritance is predicted using sensitive dosage calculations performed at sites where the parental genotypes differ. RHDO is not currently offered to consanguineous couples owing to the shared haplotype between parents. Here we test the expansion of RHDO for AR monogenic conditions to include consanguineous couples. The existing sequential probability ratio test analysis pipeline was modified to apply to SNPs where both parents are heterozygous for the same genotype. Quality control thresholds were developed using 33 nonconsanguineous cases. The performance of the adapted RHDO pipeline was tested on 8 consanguineous cases. The correct fetal genotype was predicted by our revised RHDO approach in all conclusive cases with known genotypes (n = 5). Haplotype block classification accuracies of 94.5% and 93.9% were obtained for the nonconsanguineous and consanguineous case cohorts, respectively. Our modified RHDO pipeline correctly predicts the genotype in fetuses from consanguineous families, allowing the potential to expand access to NIPD services for these families.

COVID-19 Infection During Pregnancy and Hearing Loss in Infants: A Clinical Study.

To find the prevalence of hearing loss in children born to mothers who had COVID-19 infection during pregnancy. This was a prospective observational study conducted on 1960 babies born to mothers who were COVID positive during their pregnancy .All children born to RTPCR positive COVID-19 pregnant women were included in the study and babies who had any other risk factor for neonatal SNHL were excluded from the study. All the babies were subjected to OAE, and if it came pass, the test was repeated 2 weeks later. Those patients with repeat OAE also as refer were subjected to Brainstem Evoked Response Audiometry and findings correlated. The study included 1960 neonates who were subjected to neonatal hearing screening by OAE. There were 1020 males (52.04%) and 940(47.96%) females and 80 cases of consanguinity. Fifty babies were excluded due to comorbidities. In the initial OAE test 380 neonates failed (19.9%) following which BERA was done and ten patients was found to Sensorineural hearing loss. The prevalence of hearing loss in our study on babies born to mothers with COVID-19 infection during pregnancy is 0.005. Although these primary results from our study does not indicate any immediate effect of SARS-COV-2 maternal infection on neonatal hearing. More children need to be tested and followed up over an extended period of time to detect any possible delayed auditory effects. Those patients who were identified to have hearing loss in our study will have to be on long term follow-up as we see long terms effects on cognition, memory, heart health, etc. in COVID survivors. Level 1.

Ectrodactyly-ectodermal dysplasia-clefting syndrome. Prenatal prospective ultrasound diagnosis.

Prenatal diagnosis of the Ectrodactyly-Ectodermal dysplasia-clefting (EEC) syndrome has been based upon the detection of ectrodactyly, in association with facial clefting and/or positive family history. Our aim is to describe other ultrasonographic features indicating the presuntive diagnosis, regardless of genetic diagnosis, especially in cases of negative family history. A case report and a review of the literature was assessed. Our case report showed a singleton foetus "lobster claw" deformities of hands and feet. Paternal history revealed bilateral agenesia of two fingers. Through literature, 15 case reports of prenatal diagnosis of EEC syndrome were found, 14 of which were eligible for our systematic review. The 33% of cases (5/15) had a familiar history of EEC, thus, we found one case of consanguinity of parents. Anomalies EEC-related were recognized in the 40% of cases (6/15). An association with genitourinary anomalies was found in 30% (5/15) of them. A strong suspicion of final diagnosis of EEC may be done in the presence of ectrodactyly, facial clefting and urinary malformation especially in cases of negative family history. More attention should be given to a genetic counseling, especially to understand a possible relation to other genetic syndromes.

Three cases of colon cancer in four generations of the Saudi family, caused by endogamous germline mutations.

Various research pieces of evidence have been published in recent years, establishing the increasing prevalence of early colon cancer among young people. In this background, the current study aimed to analyze the reasons behind colon cancer recurrence among endogamous consanguineous cases in four generations of a single Saud family. For this study, the authors conducted the whole-exome sequencing analysis to screen for germline mutations in DNA samples from consanguineous cases within the family. After collecting the colon samples, it was analyzed histologically and immunohistochemically with the help of Breast Cancer antibodies (BRCA2 and 1 correspondingly) and H&M staining (hematoxylin and eosin). For this study, 26 at-risk consanguineous cases were considered. Three cases were diagnosed with malignant colon cancer, two with breast cancer, and 17 with germline mutations, yet remain unaffected by cancerous tumors. The rest, four consanguineous cases, are healthy and non-carriers of the mutations. However, as per the exome analysis outcomes, 15 cases inherited germline mutations in nine genes. Nine substitution mutations were present in six of the nine inherited genes in these inherited germline mutations. Furthermore, it also presented six insertion and deletion frameshift mutations in five of nine inherited genes. The immunohistochemical staining process achieved positive staining outcomes for BRCA1 and 2. Therefore, germline mutations inherited from the nine genes of endogamous consanguineous cases of mutation carriers remain the primary reason behind colon cancer recurrence in the same family.

SNP chromosome microarray genotyping for detection of uniparental disomy in the clinical diagnostic laboratory

Single nucleotide polymorphism (SNP) chromosome microarray is well established for investigation of children with intellectual deficit/development delay and prenatal diagnosis of fetal malformation but has also emerged for uniparental disomy (UPD) genotyping. Despite published guidelines on clinical indications for testing there are no laboratory guidelines published for performing SNP microarray UPD genotyping. We evaluated SNP microarray UPD genotyping using Illumina beadchips on family trios/duos within a clinical cohort (n=98) and then explored our findings in a post-study audit (n=123). UPD occurred in 18.6% and 19.5% cases, respectively, with chromosome 15 most frequent (62.5% and 25.0%). UPD was predominantly maternal in origin (87.5% and 79.2%), highest in suspected genomic imprinting disorder cases (56.3% and 41.7%) but absent amongst children of translocation carriers. We assessed regions of homozygosity among UPD cases. The smallest interstitial and terminal regions were 2.5 Mb and 9.3 Mb, respectively. We found regions of homozygosity confounded genotyping in a consanguineous case with UPD15 and another with segmental UPD due to non-informative probes. In a unique case with chromosome 15q UPD mosaicism, we established the detection limit of mosaicism as ∼5%. From the benefits and pitfalls identified in this study, we propose a testing model and recommendations for UPD genotyping by SNP microarray.

ML Flow serological test: complementary tool in leprosy

BackgroundThe evaluation of household contacts of leprosy cases allows the early diagnosis of new cases. ObjectiveTo associate the results of the ML Flow test with the clinical characteristics of leprosy cases and to verify their positivity in household contacts, in addition to describing the epidemiological profile of both. MethodsProspective study with patients diagnosed over the course of one year (n = 26), without prior treatment, and their household contacts (n = 44) in six municipalities in northwestern São Paulo, Brazil. ResultsThere was a predominance of men among the leprosy cases, of 61.5% (16/26); 77% (20/26) were over 35 years old; 86.4% (22/26) were multibacillary; 61.5% (16/26) had a positive bacilloscopy; and 65.4% (17/26) had no physical disability. The ML Flow test was positive in 53.8% (14/26) of the leprosy cases and was associated with those who had a positive bacilloscopy and were diagnosed as multibacillary (p-value <0.05). Among the household contacts, 52.3% (23/44) were women and aged over 35 years; 81.8% (36/44) had been vaccinated with BCG ‒ Bacillus Calmette-Guérin. The ML Flow test was positive in 27.3% (12/44) of household contacts, all of whom lived with multibacillary cases; seven lived with positive bacilloscopy cases and six with consanguineous cases. Study limitationsDifficulty in convincing the contacts to undergo the evaluation and collection of the clinical sample. ConclusionThe ML Flow test, when positive in household contacts, can help the identification of cases that require more attention by the health team, as it indicates a predisposition to disease development, especially when they are household contacts of multibacillary cases, with positive bacilloscopy and consanguineous. The ML Flow test also helps in the correct clinical classification of the leprosy cases.

Consanguinity and severity of primary congenital glaucoma

To evaluate the severity of primary congenital glaucoma (PCG) among children born of consanguineous marriage. In this case-control study, the medical records of unrelated consanguineous patients and unrelated nonconsanguineous (control) PCG patients seen at a single tertiary eye care facility were retrospectively reviewed. Those with a minimum of 5 years' follow-up were included. Data collected included age at presentation, corneal diameter, axial length, corneal haze at presentation and its persistence after surgery, need for repeat surgery, and final visual acuity. A total of 130 PCG patients were included: 30 patients born of consanguineous marriage and 100 nonconsanguineous control patients. The median age of presentation for consanguineous cases was 3 months (range, 1-36) compared with 10 months (range, 2-24) for nonconsanguineous cases (P < 0.001). Mean corneal diameter for consanguineous cases was 13 ± 0.82 mm and for nonconsanguineous cases was 12.41mm ± 1.18 mm (P = 0.002). Consanguineous cases also had a significantly higher prevalence of corneal haze persisting after surgery (P < 0.001) and need for repeat IOP-lowering surgery (P = 0.039). The consanguineous group had 44 eyes (73%) with severe PCG compared with 69 (34.5%) in the nonconsanguineous group (P < 0.001). In this study cohort, children with PCG born of consanguineous parents were more severely affected at presentation compared with children born of nonconsanguineous parents; they also had poorer outcomes with IOP-lowering surgery independent of severity at presentation. It is however possible that a founder effect with consanguinity over multiple generations could account for our observations.

Familial Mediterranean fever in the pediatric population.

Familial Mediterranean fever (FMF) is the most frequent autoinflammatory disorder characterized by short, repeated, and self-limiting crises of fever and serositis. The disease was described as autosomal recessive hereditary transmission secondary to variants of the MEFV (MEditerranean FeVer) gene, even though a variable proportion of patients only present a heterozygous variant. FMF is very common in certain ethnic groups (Turkish, Armenian, Arab, and Jewish), even though it has been described throughout the Mediterranean and elsewhere in the world. The clinical manifestations are variable, with secondary amyloidosis being the most serious complication of the disorder. Treatment and prophylaxis are mainly based on the administration of colchicine, which prevents the crises and avoids complications in most cases. This study reviews the course of seven pediatric patients diagnosed with FMF during the period 2010-2018 at a district hospital. Most of the patients were of Caucasian origin, with onset at an early age in the form of fever as the main symptom, and some patients moreover presented less frequent manifestations (pericardial effusion, sensorineural hearing loss). Two cases presented plasmatic amyloid A protein elevation that subsided with the treatment. All the patients initially received colchicine, and one of them required prescription of anakinra, which was replaced by canakinumab due to a serious adverse reaction. There were no cases of consanguinity, and all the patients were of Mediterranean origin. The subjects showed a favorable course over the years, which was attributed to the early diagnosis and treatment provided.

A Protocol for Preconceptional Screening of Consanguineous Couples Using Whole Exome Sequencing.

Genetic studies performed in consanguineous couples suggest that the reproductive risk that distinguish them from other couples in the general population is related to autosomal recessive (AR) diseases. This risk is scattered among the thousands of known and potential AR diseases. Thus, for effective preconceptional screening of consanguineous couples it is necessary a test that encompasses the largest number of genes possible. For that reason, we decided to create a protocol based on whole exome sequencing (WES). We sequenced completely the exomes of 39 consanguineous couples at high coverage (∼100×). Applying bioinformatics filters, we could detect genetic variants that were simultaneously present in both members of the couple in all genes listed in the Clinical Genomics Database as causally related to AR diseases. Shared variants were then assessed for pathogenicity. For non-truncating variants (missense and in-frame indels) we considered as pathogenic or likely pathogenic only the variants included as such in the ClinVar database. Shared truncating variants (frameshift, non-sense, and canonical splice variants) were considered likely pathogenic when loss-of-function was a known mechanism of disease. The 39 consanguineous cases included two couples with a coefficient of genetic relationship (CGR) of 0.25, 26 couples with a CGR of 0.125, three couples with a CGR of 0.0625 and eight couples with a CGR of 0.03125. In 21 of the 39 couples (53.8%) we ascertained sharing of heterozygosity for at least one variant considered pathogenic or likely pathogenic for an AR disease. In eight couples we found sharing of heterozygosity for at least two pathogenic variants. Once the specific pathogenic variant was identified, it became possible for the couple to undergo prenatal diagnosis or, if desired, preimplantation genetic diagnosis (PGD) involving in vitro fertilization and embryo screening. In conclusion, our results demonstrate that preconceptional screening by WES is a useful new procedure that should be incorporated in the genetic counseling of all consanguineous couples.

Acyanotic Truncus Arteriosus Type 4 in a Sudden Infant Death: A Case Report

A congenital cyanotic heart defect such as Truncus Arteriosus (TA) is rare and is represented by a single arterial trunk that develops from the heart and gives rise to the pulmonary trunk in several manners. TA comprises 0.7% of all complex congenital heart malformations caused by numerous aetiologies, with the majority being genetic in origin. This malformation can be recognised in the prenatal period so that further medical intervention can be advocated. There are four types of the defect based on the Collett-Edwards classification. Type 4 is a rare form in which the pulmonary arteries are non-existent. Therefore, the lungs are supplied by major aortopulmonary collateral arteries. It may also describe this anatomical picture as pulmonary atresia with VSD. We report here a unique case of truncus arteriosus type 4 in an apparently well-thriving and acyanotic 6-month-old male infant. The deceased was presented with a brief history of inconsolable cry shortly before his demise and the underlying cardiac abnormalities were discovered at autopsy. A meticulous post-mortem examination elucidates a better diagnosis approach. Genetic counselling can be offered to parents in recurrent cases, such as cases of consanguinity.

Human inbreeding has decreased in time through the Holocene

The history of human inbreeding is controversial.1 In particular, how the development of sedentary and/or agricultural societies may have influenced overall inbreeding levels, relative to those of hunter-gatherer communities, is unclear.2-5 Here, we present an approach for reliable estimation of runs of homozygosity (ROHs) in genomes with ≥3× mean sequence coverage across >1 million SNPs and apply this to 411 ancient Eurasian genomes from the last 15,000 years.5-34 We show that the frequency of inbreeding, as measured by ROHs, has decreased over time. The strongest effect is associated with the Neolithic transition, but the trend has since continued, indicating a population size effect on inbreeding prevalence. We further show that most inbreeding in our historical sample can be attributed to small population size instead of consanguinity. Cases of high consanguinity were rare and only observed among members of farming societies in our sample. Despite the lack of evidence for common consanguinity in our ancient sample, consanguineous traditions are today prevalent in various modern-day Eurasian societies,1,35-37 suggesting that such practices may have become widespread within the last few millennia.

Neurofibromatosis Type 1 or Von Recklinghausen Disease: About Three Cases to the National Hospital of Niamey and Literature Review

We report three cases of neurofibromatosis type 1 disease with literature review, collected in the department of neurology and internal medicine from National Hospital of Niamey (HNN). Two of them were men and the first signs were noted by the mother at the birth in 2 cases. Only one case of consanguinity was observed. Clinically, light brown spots on the skin, neurofibromas, Lisch nodules were constantly observed. Histopathological’s exam confirmed neurofibromas. Moreover, cutaneous and ophthalmological manifestations lead to the diagnostic. Two cases of orthopedic complications were observed: one scoliosis and one Congenital dysplasia of the long bones. There was no specific treatment. Neurofibromatosis type 1 or von Recklinghausen’s disease is the most frequent phacomatosis and its diagnosis is usually composed of a set of clinical criteria of the National Institute Health (Bethesda, 1988).

Improved Diagnosis of Rare Disease Patients through Systematic Detection of Runs of Homozygosity

Autozygosity is associated with an increased risk of genetic rare disease, thus being a relevant factor for clinical genetic studies. More than 2400 exome sequencing data sets were analyzed and screened for autozygosity on the basis of detection of >1 Mbp runs of homozygosity (ROHs). A model was built to predict if an individual is likely to be a consanguineous offspring (accuracy, 98%), and probability of consanguinity ranges were established according to the total ROH size. Application of the model resulted in the reclassification of the consanguinity status of 12% of the patients. The analysis of a subset of 79 consanguineous cases with the Rare Disease (RD)–Connect Genome-Phenome Analysis Platform, combining variant filtering and homozygosity mapping, enabled a 50% reduction in the number of candidate variants and the identification of homozygous pathogenic variants in 41 patients, with an overall diagnostic yield of 52%. The newly defined consanguinity ranges provide, for the first time, specific ROH thresholds to estimate inbreeding within a pedigree on disparate exome sequencing data, enabling confirmation or (re)classification of consanguineous status, hence increasing the efficiency of molecular diagnosis and reporting on secondary consanguinity findings, as recommended by American College of Medical Genetics and Genomics guidelines.

Rett Syndrome without MECP2 Mutation in a Pakistani Girl

&#x0D; &#x0D; &#x0D; Rett syndrome is a rare inherited neurodegenerative disease which mostly affects females but has a lethal impact on males. Rett syndrome is mostly caused by mutations of Methyl CpG binding protein-2 (MECP2) gene located on chromosome Xq28. A 7-year girl from a consanguineous Pakistani family presented with history of abnormal social behavior, tonic colonic seizures, limb'sataxia, intellectual disability, growth retardation and speech abnormalities. Physical and neurological examinations established likely clinical features of Rett syndrome with abnormal electroencephalogram (EEG). Genetic testing of MECP2 gene did not identify any functional nucleotide variation indicating the involvement of another gene mutation in this patient.A consanguineous case of Rett syndrome did not carry the mutation of MECP2 gene. Due to heterogeneity of the phenotype, it is proposed that there might be involvement of another locus for this disease. In future, targeted next generation sequence can be helpful to identify the causative mutation in this patient.&#x0D; &#x0D; &#x0D;

The molecular landscape of osteogenesis imperfecta in a Brazilian tertiary service cohort.

Defects in type 1 collagen reportedly account for 85-90% of osteogenesis imperfecta (OI) cases, but most available molecular data has derived from Sanger sequencing-based approaches in developed countries. Massively parallel sequencing (MPS) allows for systematic and comprehensive analysis of OI genes simultaneously. Our objective was to obtain the molecular diagnosis of OI in a single Brazilian tertiary center cohort. Forty-nine individuals (84% adults) with a clinical diagnosis of OI, corresponding to 30 sporadic and 8 familial cases, were studied. Sixty-three percent had moderate to severe OI, and consanguinity was common (26%). Coding regions and 25-bp boundaries of 15 OI genes (COL1A1, COL1A2, IFITM5 [plus 5'UTR], SERPINF1, CRTAP, P3H1, PPIB, SERPINH1, FKBP10, PLOD2, BMP1, SP7, TMEM38B, WNT1, CREB3L1) were analyzed by targeted MPS and variants of interest were confirmed by Sanger sequencing or SNP array. A molecular diagnosis was obtained in 97% of cases. COL1A1/COL1A2 variants were identified in 71%, whereas 26% had variants in other genes, predominantly FKBP10, PLOD2, and SERPINF1. A potential digenic interaction involving P3H1 and WNT1 was identified in one case. Phenotypic variability with collagen defects could not be explained by evident modifying variants. Four consanguineous cases were associated to heterozygous COL1A1/COL1A2 variants, and two nonconsanguineous cases had compound PLOD2 heterozygosity. Novel disease-causing variants were identified in 29%, and a higher proportion of non-collagen defects was seen. Obtaining a precise diagnosis of OI in underrepresented populations allows expanding our understanding of its molecular landscape, potentially leading to improved personalized care in the future.

Análise epidemiológica das fissuras labiais e/ou palatinas no município de Feira de Santana: estudo de corte transversal

INTRODUÇÃO: As fissuras labiais e/ou palatinas representam 65% das anomalias craniofaciais e constituem um problema de saúde pública, devido às diversas implicações que geram ao portador. OBJETIVOS: Descrever o perfil epidemiológico dos portadores de fissura labial e/ou palatina, naturais de Feira de Santana, atendidos no Centro de Reabilitação de Anomalias Craniofaciais do Hospital Santo Antônio (Salvador-BA), no período de 2008 a 2013. MATERIAL E MÉTODO: Caracteriza-se como estudo epidemiológico observacional, descritivo e retrospectivo, realizado através das informações dos prontuários do referido centro. Dezoito prontuários compuseram a amostra final deste estudo. Os dados foram submetidos à análise descritiva no programa SPSS, versão 17.0. RESULTADOS: As fissuras labiais e/ou palatinas foram encontradas, principalmente, em indivíduos do sexo feminino (66.7%); 50% chegou ao centro com menos de 1 ano; 90,3% de procedência urbana e 61,5% possuía renda familiar mensal de 1-3 salários mínimos. Prevaleceram as fissuras transforame incisivo unilateral (27,7%). Nenhum dos indivíduos havia sido submetido à cirurgia antes de ingressar ao serviço; 88% realizou tratamento cirúrgico no referido centro, sendo as queiloplastias (40%) e as palatoplastias (36%) as cirurgias mais realizadas. A maioria (71,4%) das mães dos portadores apresentaram idade entre 26-34 anos no momento da concepção; 53,8% possuía nível médio de escolaridade e 44,4% utilizou medicamentos durante a gestação. Um caso de consanguinidade foi relatado. CONCLUSÃO: Os resultados encontrados apontam a necessidade de desenvolver programas de prevenção e tratamento multiprofissional direcionado aos indivíduos com fissura labial e/ou palatina, naturais da cidade de Feira de Santana e microrregiões.

The utility of whole exome sequencing in diagnosing neurological disorders in adults from a highly consanguineous population

There is increasing evidence that whole exome sequencing (WES) has a high diagnostic yield and is cost-efficient for individuals with neurological phenotypes. However, there is limited data on the use of WES in non-Western populations, including populations with a high rate of consanguinity. Retrospective chart review was performed on 24 adults with undiagnosed neurological symptoms evaluated in genetics and neurology clinics in a tertiary care facility on the Arabian Peninsula, and had WES between 2014 and 2016. Definitive diagnoses were made in 13/24 (54%) of cases. Of these, 5/13 (38%) revealed novel pathogenic variants. Of the known 19/24 (79%) consanguineous cases, diagnostic rate was slightly higher, 11/19 (58%) as compared to 2/5 (40%) among non-consanguineous cases. Autosomal recessive disorders comprised 10/13 (77%) of molecular diagnoses, all found to be due to homozygous pathogenic variants among consanguineous cases. WES in this cohort of adults with neurological symptoms had a high diagnostic rate likely due to high consanguinity rates in this population, as evidenced by the high diagnostic rate of homozygous pathogenic variants.