Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms.

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.

Urogenital and pelvic complications in the Ehlers-Danlos syndromes and associated hypermobility spectrum disorders: A scoping review.

The Ehlers-Danlos syndromes (EDS) and associated hypermobility spectrum disorders (HSD) are a heterogenous group of connective tissue disorders associated with significant morbidity. The urogenital aspects of these disorders are understudied and there is little guidance on the prevalence, types, or outcomes of urogenital complications in EDS/HSD. Our objective was to perform a scoping review to characterize and synthesize the literature reporting urogenital and pelvic complications in EDS/HSD patients. We performed a systematic search of three databases (Medline, CINAHL, Embase) to January 2019. English language, full-text articles reporting on urogenital or pelvic complications in EDS/HSD were included. A total of 105 studies were included (62 case reports/series, 43 observational) involving patients with hypermobile (23%), vascular (20%), classical (12%) EDS, and HSD (24%). Some studies looked at multiple subtypes (11%) or did not report subtype (33%). Reported complications included urinary (41%), gynecological (36%), obstetrical (25%), renal (9%), and men's health problems (7%), with some studies reporting on multiple areas. Urinary and gynecological complications were most prevalent in patients with HSD, while a broad range of complications were reported in EDS. While further research is required, results suggest a higher index of suspicion for urogenital problems is probably warranted in this population.

Evaluation and classification of severity for 176 genes on an expanded carrier screening panel.

BACKGROUND: Disease severity is important when considering genes for inclusion on reproductive expanded carrier screening (ECS) panels. We applied a validated and previously published algorithm that classifies diseases into four severity categories (mild, moderate, severe, and profound) to 176 genes screened by ECS. Disease traits defining severity categories in the algorithm were then mapped to four severity-related ECS panel design criteria cited by the American College of Obstetricians and Gynecologists (ACOG). METHODS: Eight genetic counselors (GCs) and four medical geneticists (MDs) applied the severity algorithm to subsets of 176 genes. MDs and GCs then determined by group consensus how each of these disease traits mapped to ACOG severity criteria, enabling determination of the number of ACOG severity criteria met by each gene. RESULTS: Upon consensus GC and MD application of the severity algorithm, 68 (39%) genes were classified as profound, 71 (40%) as severe, 36 (20%) as moderate, and one (1%) as mild. After mapping of disease traits to ACOG severity criteria, 170 out of 176 genes (96.6%) were found to meet at least one of the four criteria, 129 genes (73.3%) met at least two, 73 genes (41.5%) met at least three, and 17 genes (9.7%) met all four. CONCLUSION: This study classified the severity of a large set of Mendelian genes by collaborative clinical expert application of a trait-based algorithm. Further, it operationalized difficult to interpret ACOG severity criteria via mapping of disease traits, thereby promoting consistency of ACOG criteria interpretation.

Expanding the SPECC1L mutation phenotypic spectrum to include Teebi hypertelorism syndrome.

Teebi hypertelorism syndrome is a rare autosomal dominant disorder that has eluded a molecular etiology since first described in 1987. Here we report on two unrelated families with a Teebi hypertelorism-like syndrome and Teebi hypertelorism phenotype who have missense mutations in Sperm Antigen With Calponin Homology And Coiled-Coil Domains (SPECC1L), previously associated with oblique facial clefting and Opitz G/BBB syndrome. The first patient and his affected mother were previously-reported by Hoffman et al. in this journal as a new syndrome resembling Teebi hypertelorism and Aarskog syndromes in 2007. This patient had hypertelorism, sagittal and coronal craniosynostosis, ptosis, natal teeth, unusual umbilicus, shawl scrotum, small hands, and feet, with grossly normal development. Our second patient had classic Teebi hypertelorism syndrome with hypertelorism and a giant umbilical hernia. Patient one and his affected mother had a c.1260G>C:p.E420D variant and patient two had a de novo c.1198_1203delATACAC:p.I400_H401del variant in SPECC1L. We review the phenotypic findings in the previously-published Teebi hypertelorism syndrome patients, and the Opitz G/BBB patients with SPECC1L mutations. In addition we emphasize the findings of aortic root dilation and craniosynostosis in these patients, which should be considered in their management.

The Ashkenazi Jewish carrier screening panel: evolution, status quo, and disparities.

OBJECTIVE: Although prenatal/preconception carrier screening recommendations for individuals of Ashkenazi Jewish descent (AJ) were published by American College of Medical Genetics and Genomics (2008) and American College of Obstetrics and Gynecology (2009), scientific advances have led to widely varied screening panels. Mutation carrier frequencies are sometimes based on small, homogeneous AJ populations. This study sought to update the state of AJ screening for the obstetrician by assessing laboratory screening panel compositions as well as assessing literature and laboratory carrier frequencies for common AJ mutations. METHODS: A literature review (1991-2013) was performed for AJ disease carrier frequencies. AJ screening data from six screening laboratories were collected. AJ panel composition was compared across 16 commercial and academic laboratories. RESULTS: Overall literature and laboratory carrier frequencies of AJ mutations were similar, although the Walker-Warburg syndrome laboratory carrier frequency was almost twice that in the literature. Laboratory AJ disease panel composition varied widely, from 8 to 25 diseases. CONCLUSIONS: Current AJ panels vary widely by laboratory, resulting in disparate levels of screening. Consideration of an updated professional standard for prenatal/preconception AJ screening based on carrier frequency rates, level of disease burden, availability of screening, and cost of technology may be useful in providing equitable and appropriate care for those planning a pregnancy.

More than just skin deep: faciocutaneous clues to genetic syndromes with malignancies.

Genetic syndromes with dermatologic findings and multisystemic involvement (e.g., visceral cancer predisposition) are underrecognized. Patients may have incomplete penetrance and variable expressivity; some patients may solely exhibit subtle skin signs, which create a diagnostic challenge for physicians. Interdisciplinary diagnostic knowledge is required for the early diagnosis and monitoring of patients with these syndromes. Cutaneous changes in the face-one of the most highly exposed areas-can be easily noticed by patients themselves, their families and friends, and physicians; these changes may serve as early indicators of genetic syndromes with malignancies. In this article, we present examples of genetic syndromes with malignancies for which a thorough faciocutaneous examination is helpful in establishing a diagnosis. These examples include lentiginosis-related syndromes (e.g., Peutz-Jeghers syndrome, Carney complex), photosensitivity-related syndromes (Bloom syndrome, Rothmund-Thomson syndrome), and hamartoma-related syndromes (Cowden syndrome, multiple endocrine neoplasia syndrome, tuberous sclerosis complex, Gardner syndrome, Muir-Torre syndrome). The characteristics of these faciocutaneous clues are summarized and discussed. Objective evaluation of these faciocutaneous clues in combination with other clinical information (e.g., family history, histopathological findings, combination with other concomitant faciocutaneous lesions) is emphasized to narrow the diagnosis. The list of genetic syndromes with faciocutaneous manifestations is still expanding. Increased awareness of faciocutaneous markers can alert physicians to underlying syndromes and malignancies, render earlier screening and detection of associated medical issues, and allow for genetic counseling of family members.

Neonatal arrhythmias in Turner syndrome: a case report and review of the literature.

BACKGROUND: While left-sided congenital heart defects have been well described in females with Turner syndrome (45, X), the literature is scarce regarding arrhythmias in this patient population. CASE SUMMARY: A full-term neonate referred to cardiology was found to have a non-apex forming left ventricle and partial anomalous pulmonary venous return. During the echocardiogram, she developed atrial flutter, followed by orthodromic reentrant supraventricular tachycardia (SVT). She was started on propranolol and eventually switched to sotalol due to breakthrough SVT. A genetics evaluation revealed Turner syndrome with complete monosomy X (45, X). The patient is now 18 months old and has not had any further arrhythmias. DISCUSSION: We present a rare case of atrial flutter followed by supraventricular tachycardia in a neonate with Turner syndrome and left-sided heart defects. This case highlights the importance of early and precise investigation of cardiac abnormalities in neonatal patients, especially among females with Turner syndrome given their relatively higher risk of cardiovascular disease compared to the general population.

Type I hyperprolinemia: genotype/phenotype correlations.

Type I hyperprolinemia (HPI) is an autosomal recessive disorder associated with cognitive and psychiatric troubles, caused by alterations of the Proline Dehydrogenase gene (PRODH) at 22q11. HPI results from PRODH deletion and/or missense mutations reducing proline oxidase (POX) activity. The goals of this study were first to measure in controls the frequency of PRODH variations described in HPI patients, second to assess the functional effect of PRODH mutations on POX activity, and finally to establish genotype/enzymatic activity correlations in a new series of HPI patients. Eight of 14 variants occurred at polymorphic frequency in 114 controls. POX activity was determined for six novel mutations and two haplotypes. The c.1331G>A, p.G444D allele has a drastic effect, whereas the c.23C>T, p.P8L allele and the c.[56C>A; 172G>A], p.[Q19P; A58T] haplotype result in a moderate decrease in activity. Among the 19 HPI patients, 10 had a predicted residual activity <50%. Eight out of nine subjects with a predicted residual activity > or = 50% bore at least one c.824C>A, p.T275N allele, which has no detrimental effect on activity but whose frequency in controls is only 3%. Our results suggest that PRODH mutations lead to a decreased POX activity or affect other biological parameters causing hyperprolinemia.

Complexities of Clinical Genetics Consultation: An Interprofessional Clinical Skills Workshop.

Introduction: Advances in genomic medicine contribute to increased demand for clinical genetics services and require physicians to understand the interprofessional practice of this field. Medical students receive a foundation in genetics during preclinical studies, but variability in clinical experience may limit knowledge of and recruitment into this clinical specialty. In this resource, we describe an approach for simulating exposure to the practice of clinical genetics during the core pediatrics clerkship. Methods: Prior to class, students researched and considered a mock genetics case. In class, each of four small groups discussed two cases demonstrating varied presentations, with facilitation by genetic counseling students. Each case highlighted the variability in presentation, testing, management strategies, and psychosocial issues of a genetics case. Groups reported out to the class, and individuals completed an anonymous evaluation survey. Results: Surveys were distributed to nine of 10 pilot sessions (210 of 235 students) with a response rate of 48%. Students frequently reported no previous exposure to seeing patients with genetics professionals, indicated a preference for learning in case discussion format over traditional lectures, and felt the format helped them apply clinical skills and reasoning. Medical students appreciated the opportunity to interact with genetic counseling students in an interdisciplinary setting and desired further educational opportunities regarding delivering complex information to patients and their families. Discussion: This session expanded exposure to clinical genetics content and professionals, serving as an important foundation for further development of genetic knowledge during clinical training.

Population-based Tay-Sachs screening among Ashkenazi Jewish young adults in the 21st century: Hexosaminidase A enzyme assay is essential for accurate testing.

Tay-Sachs disease (TSD) carrier screening, initiated in the 1970s, has reduced the birth-rate of Ashkenazi Jews with TSD worldwide by 90%. Recently, several nationwide programs have been established that provide carrier screening for the updated panel of Jewish genetic diseases on college campuses and in Jewish community settings. The goals of this study were to determine the performance characteristics of clinical TSD testing in college- and community-based screening programs and to determine if molecular testing alone is adequate in those settings. Clinical data for TSD testing were retrospectively anonymized and subsequently analyzed for 1,036 individuals who participated in these programs. The performance characteristics of the serum and the platelet Hexosaminidase assays were compared, and also correlated with the results of targeted DNA analysis. The serum assay identified 29 carriers and the platelet assay identified 35 carriers for carrier rates of 1/36 and 1/29, respectively. One hundred sixty-nine samples (16.3%) were inconclusive by serum assay in marked contrast to four inconclusive samples (0.4%) by the platelet assay. Molecular analysis alone would have missed four of the 35 carriers detected by the platelet assay, yielding a false negative rate of 11.4% with a sensitivity of 88.6%. Based on the results of this study, platelet assay was superior to serum with a minimal inconclusive rate. Due to changing demographics of the Ashkenazi Jewish population, molecular testing alone in the setting of broad-based population screening programs is not sufficient, and biochemical analysis should be the assay of choice.

Novel homozygous OPA3 mutation in an Afghani family with 3-methylglutaconic aciduria type III and optic atrophy.

Purpose: To describe and distinguish clinical phenotypes with the overlapping feature of optic atrophy caused by distinct mutations in the same gene, OPA3. We report 3 affected siblings in a consanguineous family harboring a novel OPA3 mutation causing 3-methylglutaconic aciduria type III with optic atrophy.Methods: Retrospective case series.Results: Three siblings (2 male, 1 female) among 6 children in a consanguineous Afghani family developed decreased vision from early childhood. Both parents and all extended family members were unaffected. All 3 affected siblings suffered from severe visual impairment ranging from visual acuities of 20/150 to counting fingers. All had spastic lower extremity weakness and ataxia. Two of the three affected siblings also had a history of seizures, and the female sibling had limited cognition with diffuse atrophic changes on brain MRI. Two of the three individuals also had migraine-like headaches. Urine organic acid analysis revealed mildly elevated 3-methylglutaconic acid for the male siblings. Whole exome sequencing and subsequent PCR confirmation revealed a novel variant in OPA3 (intron1, c.142 + 2_142 + 3dupTG), affecting the consensus sequence of the splice site, for which all 3 clinically affected siblings were homozygous.Discussion: Mutations in OPA3 can cause optic atrophy in a dominant pattern of inheritance associated with cataract or in a recessive pattern associated with spastic paresis and ataxia. The novel recessive mutation and clinical presentations described herein further support how different mutation types affecting OPA3 can produce distinct clinical phenotypes and underscore the critical and susceptible role of mitochondrial health in optic nerve function.

Hypotonia and Lethargy in a Two-Day-Old Male Infant.

A 2-day old term male infant was found to be hypotonic and minimally reactive during routine nursing care in the newborn nursery. At 40 hours of life, he was hypoglycemic and had intermittent desaturations to 70%. His mother had an unremarkable pregnancy and spontaneous vaginal delivery. The mother's prenatal serology results were negative for infectious risk factors. Apgar scores were 9 at 1 and 5 minutes of life. On day 1 of life, he fed, stooled, and voided well. Our expert panel discusses the differential diagnosis of hypotonia in a neonate, offers diagnostic and management recommendations, and discusses the final diagnosis.

Mutation analysis of B3GALTL in Peters Plus syndrome.

Peters Plus syndrome comprises ocular anterior segment dysgenesis (most commonly Peters anomaly), short stature, hand anomalies, distinctive facial features, and often other additional defects and is inherited in an autosomal-recessive pattern. Mutations in the beta1,3-glucosyltransferase gene (B3GALTL) were recently reported in 20 out of 20 patients with Peters Plus syndrome. In our study, B3GALTL was examined in four patients with typical Peters Plus syndrome and four patients that demonstrated a phenotypic overlap with this condition. Mutations in B3GALTL were identified in all four patients with typical Peters Plus syndrome, while no mutations were found in the remaining four patients that demonstrated some but not all characteristic features of the syndrome. The previously reported common mutation, c.660 + 1G > A, accounted for 75% of the mutant alleles in our Peters Plus syndrome population. In addition, two new mutant alleles, c.459 + 1G > A and c.230insT, were identified and predicted to result in truncated protein products. These data confirm an important role for B3GALTL in causing typical Peters Plus syndrome, and suggest that this gene may not be implicated in syndromic cases that involve Peters anomaly but lack other classic features of this complex condition.

Rhabdomyolysis in the military: recognizing late-onset very long-chain acyl Co-A dehydrogenase deficiency.

Very long-chain acyl Co-A dehydrogenase deficiency, an inborn error of lipid metabolism, is commonly thought of as a disease of infancy or early childhood. However, several cases of late-onset very long-chain acyl Co-A dehydrogenase have been reported. This report of two military men who survived basic training before their disease presentation broadens the spectrum of late-onset disease, presents two previously unreported mutations, and demonstrates the fine line between athletic, active lifestyle and severe disease presentation.

OTX2 duplication is implicated in hemifacial microsomia.

Hemifacial microsomia (HFM) is the second most common facial anomaly after cleft lip and palate. The phenotype is highly variable and most cases are sporadic. We investigated the disorder in a large pedigree with five affected individuals spanning eight meioses. Whole-exome sequencing results indicated the absence of a pathogenic coding point mutation. A genome-wide survey of segmental variations identified a 1.3 Mb duplication of chromosome 14q22.3 in all affected individuals that was absent in more than 1000 chromosomes of ethnically matched controls. The duplication was absent in seven additional sporadic HFM cases, which is consistent with the known heterogeneity of the disorder. To find the critical gene in the duplicated region, we analyzed signatures of human craniofacial disease networks, mouse expression data, and predictions of dosage sensitivity. All of these approaches implicated OTX2 as the most likely causal gene. Moreover, OTX2 is a known oncogenic driver in medulloblastoma, a condition that was diagnosed in the proband during the course of the study. Our findings suggest a role for OTX2 dosage sensitivity in human craniofacial development and raise the possibility of a shared etiology between a subtype of hemifacial microsomia and medulloblastoma.

Knowledge, attitudes, and barriers to carrier screening for the Ashkenazi Jewish panel: a Florida experience : Education and Barriers assessment for Jewish Genetic Diseases.

The knowledge, attitudes, and barriers to Jewish genetic diseases (JGDs) and screening and their relative importance in reproductive decision-making were assessed in a population-based sample of Ashkenazi Jewish young adults in Florida. These adults attended educational screening fairs hosted by The Victor Center for the Prevention of Jewish Genetic Diseases at the University of Miami. Parametric and nonparametric tests were used as appropriate to analyze data from a single group pretest/posttest design. Four hundred twelve individuals (mean age = 24.9; 54.7 % female, 45.3 % male) completed the questionnaires. Participants' level of knowledge increased from pre- to post-intervention (81.4 vs. 91.0 %; p < 0.0001). Concern about the possibility of being a carrier of a JGD was significantly higher after an educational session (5-point Likert scale mean difference = 0.45; p < 0.0001), as was their level of concern regarding having an affected child (mean difference = 0.20; p < 0.0001). The number of participants who agreed or strongly agreed that the test results would not have any influence on their reproductive behavior was lower after the session (17.2 vs. 20.8 %; p < 0.0001). This study demonstrates that an educational carrier screening program increased knowledge and elucidated awareness of the attitudes and barriers toward JGDs and carrier screening.

3q26.33-3q27.2 microdeletion: a new microdeletion syndrome?

We describe three unrelated patients of European descent carrying an overlapping 3q26.33-3q27.2 microdeletion who share common clinical features: neonatal hypotonia, severe feeding problems, specific facial features, abnormal dentition, recurrent upper airways infections, developmental delay and severe growth impairment. One of the patients carries a smaller deletion and presents a milder phenotype. We propose that 3q26.33-3q27.2 microdeletion may represent a novel condition caused by the haploinsufficiency of dosage sensitive genes, several of which are involved in brain development.