BACKGROUND: Biological similarities between inflammatory bowel disease (IBD) and familial Mediterranean fever (FMF) have been described in humans and animal models suggesting a possible common genetic basis. FMF is caused by variants in the MEFV gene which encodes pyrin, an immune regulator. This study aimed to investigate the carrier rate of disease-causing MEFV variants in children of different ethnicities diagnosed with very-early-onset IBD (VEO-IBD). METHODS: The study included 23 children diagnosed with VEO-IBD who had undergone whole exome sequencing. The exomes were evaluated for MEFV monoallelic and biallelic disease-causing variants and compared to exome sequencing data of 250 probands with suspected monogenic diseases other than IBD. RESULTS: Of the 23 children diagnosed with VEO-IBD, 12 (52%) were carriers of at least one MEFV disease-causing variant, which was threefold higher than in individuals without IBD. The most frequent variants identified were p.M694V and p.E148Q (42% each). The allelic frequency of MEFV variants was found to be higher across the VEO-IBD group in 13 of 14 ethnicities compared to the control group. CONCLUSION: The study suggests that disease-causing variants in the MEFV gene should be sought in cases of VEO-IBD. However, the clinical importance of this finding is yet to be defined. IMPACT: There are biological similarities between inflammatory bowel disease and familial Mediterranean fever, suggesting a possible genetic relationship. Children less than 6 years old clinically diagnosed with inflammatory bowel disease have a threefold higher rate of disease-causing variants in the MEFV gene than controls. Monogenic testing in children with very-early-onset inflammatory bowel disease should include a search for MEFV variants.
OBJECTIVE: Single-nucleotide variants (SNVs) are of great significance in prenatal diagnosis as they are the leading cause of inherited single-gene disorders (SGDs). Identifying SNVs in a non-invasive prenatal screening (NIPS) scenario is particularly challenging for maternally inherited SNVs. We present an improved method to predict inherited SNVs from maternal or paternal origin in a genome-wide manner. METHODS: We performed SNV-NIPS based on the combination of fragments of cell free DNA (cfDNA) features, Bayesian inference and a machine-learning (ML) prediction refinement step using random forest (RF) classifiers trained on millions of non-pathogenic variants. We next evaluate the real-world performance of our refined method in a clinical setting by testing our models on 16 families with singleton pregnancies and varying fetal fraction (FF) levels, and validate the results over millions of inherited variants in each fetus. RESULTS: The average area under the ROC curve (AUC) values are 0.996 over all families for paternally inherited variants, 0.81 for the challenging maternally inherited variants, 0.86 for homozygous biallelic variants and 0.95 for compound heterozygous variants. Discriminative AUCs were achieved even in families with a low FF. We further investigate the performance of our method in correctly predicting SNVs in coding regions of clinically relevant genes and demonstrate significantly improved AUCs in these regions. Finally, we focus on the pathogenic variants in our cohort and show that our method correctly predicts if the fetus is unaffected or affected in all (10/10, 100%) of the families containing a pathogenic SNV. CONCLUSIONS: Overall, we demonstrate our ability to perform genome-wide NIPS for maternal and homozygous biallelic variants and showcase the utility of our method in a clinical setting.
BACKGROUND: Distal Xq28 duplication, or int22h1/int22h2-mediated Xq28 duplication syndrome, leads to cognitive impairment, neurobehavioral issues, and facial dysmorphisms. Existing literature has limited information on clinical traits and penetrance. METHODS: We identified cases of distal Xq28 duplication (chrX: 154,126,575-154,709,680, GRCh37/hg19) through a review of clinical records and microarray reports from five centers, encompassing both postnatal and prenatal cases, with no prior family knowledge of the duplication. RESULTS: Our search found 47 cases across 26 families, with duplications ranging from 208 to 935 Kb. In total, 8 out of 26 index cases featured a 200-300 kb partial duplication, mainly from Armenian/Caucasian Jewish backgrounds. Most prenatal cases showed no major fetal ultrasound malformations. Of cases with known inheritance mode (15 out of 26), maternal inheritance was more common (80%). The study identified seven male carriers of the duplication from six unrelated families, indicating partial penetrance in males. CONCLUSION: Our study provides key insights into distal Xq28 duplication. Most prenatal tests showed no major fetal ultrasound issues. Maternal inheritance was common, with unaffected mothers. In the postnatal group, a balanced gender distribution was observed. Among male family members, two fathers had ADHD, one was healthy, and one brother had mild symptoms, indicating partial penetrance in males.
OBJECTIVE: This study aimed to determine the diagnostic yield of chromosomal microarray analysis (CMA) performed in cases of fetal abnormalities detected during the third trimester of pregnancy. STUDY DESIGN: A retrospective review of medical records was conducted for women who underwent amniocentesis at or beyond 28 weeks of gestation between January 2017 and February 2023. CMA results of pregnancies with abnormal sonographic findings not detected before 28 weeks were included. RESULTS: A total of 482 fetuses met the inclusion criteria. The average maternal age was 31.3 years, and the average gestational age at amniocentesis was 32.3 weeks. The overall diagnostic yield of CMA was 6.2% (30 clinically significant copy number variations [CNVs]). The yield was 16.4% in cases with two or more fetal malformations, while cases with a single anomaly revealed a diagnostic yield of 7.3%. Cases presenting isolated polyhydramnios or isolated fetal growth restriction had a lower yield of 9.3 and 5.4%, respectively. Of the 30 clinically significant cases, 19 (or 63.4%) exhibited recurrent CNVs. The remaining 11 cases (or 36.6%) presented unique CNVs. The theoretical yield of Noninvasive Prenatal Testing (NIPT) in our cohort is 2% for aneuploidy, which implies that it could potentially miss up to 70% of the significant findings that could be identified by CMA. In 80% of the fetuses (or 24 out of 30) with clinically significant CNVs, the structural abnormalities detected on fetal ultrasound examinations corresponded with the CMA results. CONCLUSION: The 6.2% detection rate of significant CNVs in late-onset fetal anomalies confirms the value of CMA in third-trimester amniocentesis. The findings underscore the necessity of CMA for detecting CNVs potentially overlooked by NIPT and emphasize the importance of thorough genetic counseling. KEY POINTS: · CMA yields 6.2% for third-trimester anomalies.. · NIPT may miss 70% of CMA findings.. · Ultrasound matched 80% of CMA results..
POT1 (Protection of Telomeres 1) is a key component of the six-membered shelterin complex that plays a critical role in telomere protection and length regulation. Germline variants in the POT1 gene have been implicated in predisposition to cancer, primarily to melanoma and chronic lymphocytic leukemia (CLL). We report the identification of POT1 p.(I78T), previously ranked with conflicting interpretations of pathogenicity, as a founder pathogenic variant among Ashkenazi Jews (AJs) and describe its unique clinical landscape. A directed database search was conducted for individuals referred for genetic counselling from 2018 to 2023. Demographic, clinical, genetic, and pathological data were collected and analyzed. Eleven carriers, 25 to 67 years old, from ten apparently unrelated families were identified. Carriers had a total of 30 primary malignancies (range 1-6); nine carriers (82%) had recurrent melanoma between the ages of 25 and 63 years, three carriers (27%) had desmoid tumors, three (27%) had papillary thyroid cancer (PTC), and five women (63% of female carriers) had breast cancer between the ages of 44 and 67 years. Additional tumors included CLL; sarcomas; endocrine tumors; prostate, urinary, and colorectal cancers; and colonic polyps. A review of a local exome database yielded an allelic frequency of the variant of 0.06% among all ethnicities and of 0.25% in AJs. A shared haplotype was found in all carriers tested. POT1 p.(I78T) is a founder disease-causing variant associated with early-onset melanoma and additional various solid malignancies with a high tumor burden. We advocate testing for this variant in high-risk patients of AJ descent. The inclusion of POT1 in germline panels for various types of cancer is warranted.
Leukemia, Lymphocytic, Chronic, B-Cell , Melanoma , Skin Neoplasms , Thyroid Neoplasms , Male , Humans , Female , Adult , Middle Aged , Aged , Melanoma/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Telomere-Binding Proteins/genetics , Skin Neoplasms/genetics , Shelterin Complex
INTRODUCTION: Microcephaly, characterized by abnormal head growth, can often serve as an initial indicator of congenital, genetic, or acquired disorders. In this study, we sought to evaluate the effectiveness of chromosomal microarray (CMA) testing in detecting abnormalities in both prenatal and postnatal cases of microcephaly. MATERIALS AND METHODS: CMA Testing: We conducted CMA testing on 87 prenatally-detected microcephaly cases and 742 postnatal cases at a single laboratory. We evaluated the CMA yield in relation to specific clinical characteristics. RESULTS: In prenatal cases, pathogenic and likely pathogenic (LP) results were identified in 4.6% of cases, a significantly higher rate compared to low-risk pregnancies. The male-to-female ratio in this cohort was 3, and the CMA yield was not influenced by gender or other clinical parameters. For postnatal cases, the CMA yield was 15.0%, with a significantly higher detection rate associated with dysmorphism, hypotonia, epilepsy, congenital heart malformations (CHM), learning disabilities (LD), and a history of Fetal growth restriction (FGR). No specific recurrent copy number variations (CNVs) were observed, and the rate of variants of unknown significance was 3.9%. CONCLUSIONS: The yield of CMA testing in prenatal microcephaly is lower than in postnatal cases (4.6% vs. 15%). The presence of microcephaly, combined with dysmorphism, hypotonia, epilepsy, CHD, LD, and FGR, significantly increases the likelihood of an abnormal CMA result.
OBJECTIVE: Significant discrepancy exists between laboratories in classification and reporting of copy number variants (CNVs). Studies exploring factors affecting prenatal CNV management are rare. Our "virtual fetus" pilot study examines these factors. METHOD: Ten prenatally diagnosed CNVs of uncertain significance (VUS) > 1Mb, encompassing OMIM-morbid genes, inherited from healthy parents, were classified by 15 MD geneticists from laboratory, prenatal, and preimplantation genetic testing (PGT) units. Geneticists addressed factors affecting classification, obligation to report, and recommendation for invasive testing or PGT. RESULTS: CNVs were classified likely benign (10.7%), VUS (74.7%), likely pathogenic (8.7%), or pathogenic (6.0%). Classification discrepancy was higher for losses versus gains. Classifying pathogenic/likely pathogenic was more common for losses (adjusted odds ratio [aOR] 10.9, 95% CI 1.55-76.9), and geneticists specializing in gynecology (aOR 4.9, 95% CI 1.03-23.3). 84.0% of respondents would report CNVs, depending on classification and family phenotype. Invasive testing in pregnancies was recommended for 29.3% of CNVs, depending on the classification and geneticist's specialization. PGT was recommended for 32.4%, depending on classification, experience years, and family's phenotype (38.0% for patients undergoing in vitro fertilization irrespectively, 26.7% otherwise). CONCLUSION: Factors affecting CNV classification/reporting are mainly dosage, family phenotype, geneticist specialization and experience. Understanding factors from our pilot study may facilitate developing an algorithm for clinical consensus and optimal management.
DNA Copy Number Variations , Fetus , Female , Pregnancy , Humans , Pilot Projects , Microarray Analysis , Phenotype
BACKGROUND: Chromosomal-microarray-analysis (CMA) may reveal susceptibility-loci (SL) of varied penetrance for autism-spectrum-disorder (ASD) and other neurodevelopmental conditions. Attitudes of women/parents to disclosure of SL during pregnancy are understudied. METHODS: A multiple-choice questionnaire was distributed to postpartum women. Data were collected on women's interest to receive prenatal genetic information with various levels of penetrance. RESULTS: Women's (n = 941) disclosure choices were dependent on the magnitude of risk: approximately 70% supported disclosure of either full or 40% penetrance, 53% supported disclosure at a 20% risk threshold, and 40% supported disclosure at 10% or less. Although most women supported, rejected or were indecisive about disclosure consistently across all risk levels, nearly one-quarter (24%) varied their responses based on penetrance, and this was associated with religiosity, education, parity and concern about fetal health (p-values <0.04). Among those who varied their choices, the risk threshold was lower among secular women (20%) than among ultraorthodox women (40%). In a multivariable analysis, ultraorthodox women were much less likely to vary their choices on ASD disclosure compared with secular women (aOR = 0.37, p < 0.001). CONCLUSION: Women's attitudes toward disclosure are influenced by the level of risk and their individual characteristics. We therefore encourage engaging women/couples in disclosure decisions regarding uncertain and probabilistic results from prenatal genomic tests.
Disclosure , Prenatal Diagnosis , Pregnancy , Female , Humans , Penetrance , Prenatal Care , Uncertainty
Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause for chronic kidney disease below age 30 years. Many monogenic forms have been discovered due to comprehensive genetic testing like exome sequencing. However, disease-causing variants in known disease-associated genes only explain a proportion of cases. Here, we aim to unravel underlying molecular mechanisms of syndromic CAKUT in three unrelated multiplex families with presumed autosomal recessive inheritance. Exome sequencing in the index individuals revealed three different rare homozygous variants in FOXD2, encoding a transcription factor not previously implicated in CAKUT in humans: a frameshift in the Arabic and a missense variant each in the Turkish and the Israeli family with segregation patterns consistent with autosomal recessive inheritance. CRISPR/Cas9-derived Foxd2 knockout mice presented with a bilateral dilated kidney pelvis accompanied by atrophy of the kidney papilla and mandibular, ophthalmologic, and behavioral anomalies, recapitulating the human phenotype. In a complementary approach to study pathomechanisms of FOXD2-dysfunction-mediated developmental kidney defects, we generated CRISPR/Cas9-mediated knockout of Foxd2 in ureteric bud-induced mouse metanephric mesenchyme cells. Transcriptomic analyses revealed enrichment of numerous differentially expressed genes important for kidney/urogenital development, including Pax2 and Wnt4 as well as gene expression changes indicating a shift toward a stromal cell identity. Histology of Foxd2 knockout mouse kidneys confirmed increased fibrosis. Further, genome-wide association studies suggest that FOXD2 could play a role for maintenance of podocyte integrity during adulthood. Thus, our studies help in genetic diagnostics of monogenic CAKUT and in understanding of monogenic and multifactorial kidney diseases.
Embryonic Structures , Forkhead Transcription Factors , Kidney Diseases , Kidney , Nephrons , Urinary Tract , Urogenital Abnormalities , Vesico-Ureteral Reflux , Adult , Animals , Humans , Mice , Genome-Wide Association Study , Kidney/abnormalities , Kidney/embryology , Kidney Diseases/genetics , Mice, Knockout , Nephrons/embryology , Transcription Factors/genetics , Urogenital Abnormalities/genetics , Vesico-Ureteral Reflux/genetics , Forkhead Transcription Factors/deficiency , Forkhead Transcription Factors/metabolism
BACKGROUND: Alport syndrome is a hereditary disorder caused by pathogenic variants in the COL4A gene, which can be inherited in an autosomal recessive, dominant, or X-linked pattern. In the Bukharian Jewish population, no founder pathogenic variant has been reported in COL4A4. METHODS: The cohort included 38 patients from 22 Bukharian Jewish families with suspected Alport syndrome who were referred the nephrogenetics clinic between 2012 and 2022. The study collected demographic, clinical, and genetic data from electronic medical records, which were used to evaluate the molecular basis of the disease using Sanger sequencing, and next-generation sequencing. RESULTS: Molecular diagnosis was confirmed in 20/38 patients, with each patient having at least one of the three disease-causing COL4A4 variants detected: c.338GA (p.Gly1008Arg), and c.871-6T>C. In addition, two patients were obligate carriers. Overall, there were 17 heterozygotes, 2 compound heterozygotes, and 3 homozygotes. Each variant was detected in more than one unrelated family. All patients had hematuria with/without proteinuria at referral, and the youngest patient with proteinuria (age 5 years) was homozygous for the c.338G>A variant. End-stage renal disease was diagnosed in two patients at the age of 38 years, a compound heterozygote for c.338G>A and c.871-6T>C. Hearing deterioration was detected in three patients, the youngest aged 40 years, all of whom were heterozygous for c.338G>A. CONCLUSION: This study unveils three novel disease-causing variants, c.3022G>A, c.871-6T>C, and c.338G>A, in the COL4A4 gene that are recurrent among Jews of Bukharian ancestry, and cause Alport syndrome in both dominant and recessive autosomal inheritance patterns.
Nephritis, Hereditary , Humans , Nephritis, Hereditary/genetics , Jews/genetics , Collagen Type IV/genetics , Pedigree , Proteinuria
BACKGROUND: The rate of clinically significant copy number variants in chromosomal microarray analysis in low-risk pregnancies is approximately 1%. However, these results include copy number variants with low and variable penetrance, although some patients might be interested only in the detection of high-penetrant variants. OBJECTIVE: This study aimed to calculate the prevalence of high-penetrant copy number variants in a large cohort of low-risk pregnancies. STUDY DESIGN: This retrospective study was performed using microarray results of pregnancies with normal ultrasound and maternal serum screening. All clinically significant (pathogenic and likely pathogenic) copy number variants were recorded. Of these, only high-penetrant findings were selected. Findings with low and medium penetrance and copy number variants with unknown clinical penetrance, including uniparental disomy of segments not related to known imprinted syndromes, mosaic aneuploidy of <50%, and segmental mosaicism, were excluded. The calculation was performed for the overall cohort, for women aged >35 years and women aged <35 years, and after omission of noninvasive prenatal screening theoretically detectable findings (trisomies 13, 18, and 21). RESULTS: Clinically significant copy number variants were detected in 118 of 7734 cases (1.50% or 1:65), and high-penetrant copy number variants were detected in 33 of 7734 cases (0.43% or 1:234). In women aged ≥35 years, the rates of high-penetrant copy number variants were 29 of 5734 cases (0.51% or 1:198) and 4 of 2000 cases (0.20% or 1:500) in women aged <35 years (P=.0747). Following the omission of 12 theoretically noninvasive prenatal screening-detectable findings, the rates of high-penetrant copy number variants declined to 21 of 7722 cases (0.27% or 1:368) in the whole cohort-18 of 5723 cases (0.31% or 1:318) in woman aged ≥35 years and 3 of 1999 cases (0.15% or 1:666) in younger women (P=.319). CONCLUSION: The risk of high-penetrant copy number variants in low-risk pregnancies exceeds the risk of miscarriage after invasive testing, even after normal noninvasive prenatal screening results. These results are of importance to genetic counselors and obstetricians, to facilitate maternal informed decision-making when considering invasive prenatal testing in low-risk pregnancies.
DNA Copy Number Variations , Prenatal Diagnosis , Pregnancy , Humans , Female , Prenatal Diagnosis/methods , Retrospective Studies , Prevalence , Chromosome Aberrations
BACKGROUND: Wilson disease is caused by pathogenic variants in the ATP7B gene which encodes a copper-transporting ATPase. AIMS: Describe a common founder pathogenic variant among Bukharan Jews and to assess its prevalence, clinical features, and outcome. METHODS: The cohort consisted of patients of Bukharan Jewish descent diagnosed with Wilson disease at a tertiary pediatric medical center in 2013-2018. Clinical and genetic data were collected and analyzed. RESULTS: Six patients from 4 unrelated families who were homozygous for the c.3784G > T p.(Val1262Phe) pathogenic variant in ATP7B were identified. Five presented with elevated aminotransferase levels, and one, with acute liver failure. Mean age at diagnosis was 8.7 years (5-12.5). Serum ceruloplasmin level was extremely low in all patients (1.9-7 mg/dL; mean 3.2(. The variant was identified in a heterozygous state in 5/153 Bukharan Jews; 2/33 from our local exome database and 3/120 healthy unrelated Bukharan Jews in another cohort, for an estimated carrier frequency of â¼1:30. CONCLUSIONS: We report a common founder pathogenic variant in the ATP7B gene among Bukharan Jews associated with severe early-onset Wilson disease. Given the clinical severity, high frequency of the variant, and being a treatable disease, its inclusion in pre-symptomatic screening in the Bukharan Jewish community should be considered. Furthermore, WD should be part of future genetic newborn screening programs in Israel and worldwide, to enable early treatment and prevention of future life-threatening complications.
Hepatolenticular Degeneration , Infant, Newborn , Humans , Child , Hepatolenticular Degeneration/genetics , Hepatolenticular Degeneration/epidemiology , Jews/genetics , Israel/epidemiology , Copper-Transporting ATPases/genetics , Genetic Testing , Heterozygote , Mutation
Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.
De Lange Syndrome , Nuclear Proteins , Humans , Nuclear Proteins/genetics , De Lange Syndrome/diagnosis , De Lange Syndrome/genetics , De Lange Syndrome/pathology , Transcription Factors/genetics , Cell Cycle Proteins/genetics , Phenotype , Mutation , Genomics , Genetic Association Studies , Transcriptional Elongation Factors/genetics , Histone Deacetylases/genetics , Repressor Proteins/genetics
Proximal 1q21 microduplication is an incomplete penetrance and variable expressivity syndrome. This study reports 28 new cases and summarizes data on phenotype, gender, and parental origin. Data on isolated proximal 1q21.1 microduplications (g. chr1:145,394,956-145,762,959 GRCh37/hg19) was retrieved in postnatal and prenatal "clinical cases" group, and prenatal "control group." The "clinical cases" cases included cases where chromosomal microarray (CMA) was performed due to congenital anomalies, autism spectrum disorder, seizures, and developmental delay/intellectual disability. The "control group" cases consisted of fetal CMA performed upon parental request despite normal nuchal translucency and anatomical second trimester fetal scans. We analyzed a local database of 27,990 cases and another cohort of 80,000 cases (including both indicated and non-indicated cases) for population frequency analysis. A total of 62 heterozygous cases were found, including 28 index cases and 34 family members. Among the index cases, 13 (9 males, 4 females) were identified in the "clinical cases" group, of which 10 had developmental abnormalities. Parental origin was tested in 9/13 cases, and all were found to be maternally inherited. In the "control group," which comprised non-affected cases, of 15 cases (10 males, 5 females), only 5/11 were maternally inherited. Four cases with clinical follow-up showed no reported neurodevelopmental abnormalities. No de-novo cases were detected, and the population frequency in both cohorts was 1:1000. Proximal 1q21.1 microduplication is a recurrent copy number variant, associated with neurodevelopmental abnormalities. It has a greater impact on males inheriting it from their mothers than females from their fathers.
Autism Spectrum Disorder , Intellectual Disability , Male , Pregnancy , Female , Humans , Autism Spectrum Disorder/genetics , Intellectual Disability/genetics , Phenotype , Chromosomes , Microarray Analysis
For decades, prenatal screening and genetic testing strategies were limited, requiring less complex decisions. Recently, however, several new advanced technologies were introduced, including chromosomal microarray analysis (CMA) and non-invasive prenatal screening (NIPS), bringing about the need to choose the most appropriate testing for each pregnancy. A worrisome issue is that opposed to the wide implementation and debates over public funding of NIPS, currently invasive testing is still recommended only in selected pregnancies with increased risk for chromosomal aberrations (according to screening tests or sonographic anomalies). This current decision-making regarding public funding for invasive and screening testing might compromise informed consent and patient's autonomy. In this manuscript, we compare several characteristics of CMA vs. NIPS, namely: the accuracy and the diagnostic scope, the risks for miscarriage and for clinically uncertain findings, the timing for testing, and pretest counselling. We argue that it must be recognized that one size might not fit all, and suggest that both options should be presented to all couples through early genetic counseling, with public funding for the specific selected test.
A significant challenge limiting the comprehensive utilization of genomic medicine is the lack of timely access to genetics specialists. Although neurologists see patients for whom genetic testing should be considered, the knowledge regarding the choice of the optimal genetic test for each case and the management of the test results are out of the scope of their everyday practice. In this review, we provide a step-by-step guide for non-geneticist physicians through the decision-making process when ordering diagnostic genetic testing for monogenic neurological diseases and when dealing with their results.
Nervous System Diseases , Physicians , Humans , Neurologists , Genetic Testing/methods , Nervous System Diseases/diagnosis , Nervous System Diseases/genetics
A short report of two male siblings born with cutis aplasia, lymphedema and intestinal lymphangiectasia, one found to carry bi-allelic variants in the TIE1 gene known to be associated with congenital lymphedema.
Ectodermal Dysplasia , Lymphangiectasis, Intestinal , Lymphedema , Humans , Male , Lymphangiectasis, Intestinal/diagnosis , Lymphangiectasis, Intestinal/genetics , Lymphangiectasis, Intestinal/complications , Ectodermal Dysplasia/genetics , Alleles , Siblings , Lymphedema/genetics
BACKGROUND: Local and worldwide prenatal charts for estimated fetal weight and postnatal charts for head circumference are gender specific. However, prenatal head circumference nomograms are not gender customized. OBJECTIVE: This study aimed to create gender-customized curves to assess between-gender head circumference differences and to study the clinical significance of using such gender-customized curves. STUDY DESIGN: A single-center retrospective study was conducted between June 2012 and December 2020. Prenatal head circumference measurements were obtained from routine estimated fetal weight ultrasound scans. Postnatal head circumference measurement at birth and gender were retrieved from computerized neonatal files. Head circumference curves were created, and the normal range was defined for the male and female subpopulations. After applying gender-specific curves, we analyzed the outcome of cases classified as microcephaly and macrocephaly according to non-gender-customized curves, which were reclassified as normal according to gender-specific curves. For these cases, clinical information and postnatal long-term outcomes were retrieved from patients' medical records. RESULTS: The cohort included 11,404 participants (6000 males and 5404 females). The curve for male head circumference was significantly higher than the female curve for all gestational weeks (P<.0001). Applying gender customized curves resulted in fewer cases of male fetuses defined as 2 standard deviations above the normal range and female fetuses defined as 2 standard deviations below of the normal range. Cases reclassified as normal head circumference after the application of gender-customized curves were not related to increased adverse postnatal outcomes. The rate of neurocognitive phenotypes was not higher than the expected rate in both male and female cohorts. Polyhydramnios and gestational diabetes mellitus were more common in the normalized male cohort, whereas oligohydramnios, fetal growth restriction, and cesarean delivery were more common in the normalized female cohort. CONCLUSION: Prenatal gender-customized curves for head circumference can reduce the overdiagnosis of microcephaly in females and macrocephaly in males. According to our results, gender-customized curves did not affect the clinical yield of prenatal measurements. Therefore, we suggest that gender-specific curves be used to avoid unnecessary workup and parental anxiety.
