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Pathogenic PHF21A variation causes PHF21A‐related neurodevelopmental disorders (NDDs). Although amorphic alleles, including haploinsufficiency, have been established as a disease mechanism, increasing evidence suggests that missense variants as well as frameshift variants extending the BHC80 carboxyl terminus also cause disease. Expanding on these, we report a proposita with intellectual disability and overgrowth and a novel de novo heterozygous PHF21A splice variant (NM_001352027.3:c.[153+1G>C];[=]) causing skipping of exon 6, which encodes an in‐frame BHC80 deletion (p.(Asn30_Gln51del)). This deletion disrupts a predicted leucine zipper domain and implicates this domain in BHC80 function and as a target of variation causing PHF21A‐related NDDs. This extension of understanding emphasizes the application of RNA analysis in precision genomic medicine practice. [ABSTRACT FROM AUTHOR]

Tandem splice acceptors (NAGNnAG) are a common mechanism of alternative splicing, but variants that are likely to generate or to disrupt tandem splice sites have rarely been reported as disease causing. We identify a pathogenic intron 23 CLTC variant (NM_004859.4:c.[3766‐13_3766‐5del];[=]) in a propositus with intellectual disability and behavioral problems. By RNAseq analysis of peripheral blood mRNA, this variant generates transcripts using cryptic proximal splice acceptors (NM_004859.4: r.3765_3766insTTCACAGAAAGGAACTAG, and NM_004859.4:r.3765_3766insAAAGGAACTAG). Given that the propositus expresses 38% the level of CLTC transcripts as unaffected controls, these variant transcripts, which encode premature termination codons, likely undergo nonsense mediated mRNA decay (NMD). This is the first functional evidence for CLTC haploinsufficiency as a cause of CLTC‐related disorder and the first evidence that the generation of tandem alternative splice sites causes CLTC‐related disorder. We suggest that variants creating tandem alternative splice sites are an underreported disease mechanism and that transcriptome‐level analysis should be routinely pursued to define the pathogenicity of such variants. [ABSTRACT FROM AUTHOR]

The Notch proteins play key roles in cell fate determination during development. Germline pathogenic variants in NOTCH1 predispose to a spectrum of cardiovascular malformations including Adams‐Oliver syndrome and a wide variety of isolated complex and simple congenital heart defects. The intracellular C‐terminus of the single‐pass transmembrane receptor encoded by NOTCH1 contains a transcriptional activating domain (TAD) required for target gene activation and a PEST domain (a sequence rich in proline, glutamic acid, serine, and threonine), regulating protein stability and turnover. We present a patient with a novel variant encoding a truncated NOTCH1 protein without the TAD and PEST domain (NM_017617.4: c.[6626_6629del];[=], p.(Tyr2209CysfsTer38)) and extensive cardiovascular abnormalities consistent with a NOTCH1‐mediated mechanism. This variant fails to promote transcription of target genes as assessed by luciferase reporter assay. Given the roles of the TAD and PEST domains in NOTCH1 function and regulation, we hypothesize that loss of both the TAD and the PEST domain results in a stable, loss‐of‐function protein that acts as an antimorph through competition with wild‐type NOTCH1. [ABSTRACT FROM AUTHOR]

Pediatric cardiomyopathies (CM) are rare and challenging to diagnose due to the complex and mixed phenotypes. With the advent of next-generation sequencing (NGS), variants in several genes associated with CM have been identified, such as Troponin C (TnC), encoded by the TNNC1 gene. De novo variants in TNNC1 have been associated with different types of CM, including dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). The American College of Medical Genetics and Genomics recently added TNNC1 to their recommended list of genes for reporting secondary findings. In this study, we report a de novo variant, c.100G > C (p.Gly34Arg) in the TNNC1 gene identified in three siblings with a diagnosis of severe DCM causing infant death for one of the siblings and stillbirth in the other two pregnancies. The identification of the same de novo variant in all affected siblings is suggestive of germline mosaicism in this family. [ABSTRACT FROM AUTHOR]

Introduction: Genome-wide sequencing (exome or whole genome) is transforming the care and management of paediatric patients with a rare disease because of its diagnostic capabilities. Genome-wide sequencing is most effective when both parents and the child are sequenced as a trio. Genetic counselling is recommended for all families considering genome-wide sequencing. Although telehealth is well established in genetic counselling for hereditary cancer and prenatal genetics, its use with genome-wide sequencing has not been well studied. The CAUSES Clinic at BC Children's and Women's Hospitals was a translational paediatric trio-based genome-wide sequencing initiative. Pre-test genetic counselling via telehealth (at a clinical site near the family's residence) was offered to families who had been previously evaluated by a clinical geneticist. We report on the first 300 families seen in the CAUSES clinic and compare health services implementation issues of families seen via telehealth versus on-site. Methods: Demographics, cost to families (travel and time), time to first appointment, complete trio sample accrual and diagnostic rates were studied. Results: Of the 300 patients, 58 (19%) were seen via telehealth and 242 (81%) were seen on-site for pre-test counselling. The mean time to completion of accrual of trio samples in the telehealth group was 56.3 (standard deviation ±87.3) days versus 18.9 (standard deviation ±62.4) days in the onsite group (p < 2.2 × 10−16). The mean per-family estimated actual or potential travel/time cost savings were greater in the telehealth group (Can$987; standard deviation = Can$1151) than for those seen on-site (Can$305; standard deviation = Can$589) (p = 0.0004). Conclusions: Telehealth allowed for access to genome-wide sequencing for families in remote communities and for them to avoid significant travel and time costs; however, there was a significant delay to accrual of the complete trio samples in the telehealth group, impacting on time of result reporting and delaying diagnoses for families for whom genome-wide sequencing was diagnostic. [ABSTRACT FROM AUTHOR]

Large single mitochondrial DNA (mtDNA) deletion syndrome is a rare inborn error of metabolism with variable heteroplasmy levels and clinical phenotype among affected individuals. Chronic progressive external ophthalmoplegia (CPEO) is the most common phenotype in adults with this form of mitochondrial disease [J Intern Med. 2020;287(6):592–608 and Biomed Rep. 2016;4(3):259–62]. The common CPEO clinical manifestations are ptosis and ophthalmoplegia. More variable phenotypic manifestations of CPEO (CPEO plus) include involvement of the peripheral nervous system and myopathy. Here, we describe a 62-year-old female with CPEO and the major mtDNA deletion present at 40% heteroplasmy, who had a coexistent previously undescribed CPEO phenotypic feature of persistent unexplained macrocytosis without anemia. Building on this case, we reviewed other major mtDNA deletion cases seen in our Adult Metabolic Diseases Clinic (AMDC) at the University of British Columbia, Vancouver, Canada, from 2016 to 2022. The major mtDNA deletion cases (n = 26) were compared with mtDNA missense variants identified in the clinic over the same period who acted as the comparison group (n = 16). Of these, the most frequent diagnosis was maternally inherited diabetes and deafness and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. Ten out of 26 (38%) of mtDNA deletion patients had macrocytosis with elevated mean corpuscular volume (MCV), median (interquartile range) of 108 fL (102–114 fL). Seven of the patients with macrocytosis had no pertinent etiology. None of the comparison group had macrocytosis. There was a significant difference (p = 0.000) between the MCV and MCH in the mtDNA deletion group compared to the comparison group. This communication sheds light on the association of macrocytosis with the mtDNA deletion syndrome. It would be of great interest to determine if the association is found in other mitochondrial disease clinic populations. [ABSTRACT FROM AUTHOR]

Background: Acid Sphingomyelinase Deficiency (ASMD) is a rare autosomal recessive disorder caused by mutations in the SMPD1 gene. This rarity contributes to misdiagnosis, delayed diagnosis and barriers to good care. There are no published national or international consensus guidelines for the diagnosis and management of patients with ASMD. For these reasons, we have developed clinical guidelines that defines standard of care for ASMD patients. Methods: The information contained in these guidelines was obtained through a systematic literature review and the experiences of the authors in their care of patients with ASMD. We adopted the Appraisal of Guidelines for Research and Evaluation (AGREE II) system as method of choice for the guideline development process. Results: The clinical spectrum of ASMD, although a continuum, varies substantially with subtypes ranging from a fatal infantile neurovisceral disorder to an adult-onset chronic visceral disease. We produced 39 conclusive statements and scored them according to level of evidence, strengths of recommendations and expert opinions. In addition, these guidelines have identified knowledge gaps that must be filled by future research. Conclusion: These guidelines can inform care providers, care funders, patients and their carers about best clinical practice and leads to a step change in the quality of care for patients with ASMD with or without enzyme replacement therapy (ERT). [ABSTRACT FROM AUTHOR]

Objective: To evaluate the impact of implementing commercial whole exome sequencing (WES) and targeted gene panel testing in pregnancies with fetal anomalies. Methods: A retrospective chart review of 124 patients with sequencing performed by commercial laboratories. Results: The diagnostic yield of WES and panel testing was 21.5% and 26%, respectively, based on likely pathogenic (LP) or pathogenic (P) variants. Forty‐two percent of exomes and 32% of panels analysed had one or more variants of uncertain significance (VUS) reported. A multidisciplinary in‐depth review of the fetal phenotype, disease phenotype, variant data, and, in some patients, additional prenatal or postnatal investigations increased the diagnostic yield by 5% for exome analysis and 6% for panel analysis. Conclusions: The diagnostic yield of WES and panel testing combined was 23% based on LP and P variants. Although the reporting of VUS contributed to a 5% increase in diagnostic yield for WES and 6% for panels, the large number of VUS reported by commercial laboratories has significant resource implications. Our results support the need for greater adherence to the recommendations on the prenatal reporting of VUS and the importance of a multidisciplinary approach that brings together clinical and laboratory expertise in prenatal genetics and genomics. Key points: What is already known about this topic? Prenatal exome sequencing in fetuses with structural anomalies identified on ultrasound increases the diagnostic yield by about 31%. What does this study add? This study demonstrates that the reporting of variants of uncertain significance (VUS) increases the diagnostic rate by 5%–6%.It illustrates the need for greater adherence to guidelines for the prenatal reporting of VUS as it varies greatly between laboratories.It emphasizes the importance of a multidisciplinary approach that brings together clinical and laboratory expertise in prenatal genetics and genomics. [ABSTRACT FROM AUTHOR]

Alternative use of short distance tandem sites such as NAGNnAG are a common mechanism of alternative splicing; however, single nucleotide variants are rarely reported as likely to generate or to disrupt tandem splice sites. We identify a pathogenic intron 5 STK11 variant (NM_000455.4:c.[735‐6A>G];[=]) segregating with the mucocutaneous features but not the hamartomatous polyps of Peutz–Jeghers syndrome in two individuals. By RNAseq analysis of peripheral blood mRNA, this variant was shown to generate a novel and preferentially used tandem proximal splice acceptor (AAGTGAAG). The variant transcript (NM_000455.4:c.734_734 + 1insTGAAG), which encodes a frameshift (p.[Tyr246Glufs*43]) constituted 36%–43% of STK11 transcripts suggesting partial escape from nonsense mediated mRNA decay and translation of a truncated protein. A review of the ClinVar database identified other similar variants. We suggest that nucleotide changes creating or disrupting tandem alternative splice sites are a pertinent disease mechanism and require contextualization for clinical reporting. Additionally, we hypothesize that some pathogenic STK11 variants cause an attenuated phenotype. [ABSTRACT FROM AUTHOR]

Fabry disease is a rare X‐linked lysosomal storage disorder caused by a deficiency in the lysosomal enzyme, galactosidase A, that can result in a progressive increase in the left ventricle (LV) wall thickness from glycosphingolipid deposition leading to myocardial fibrosis, conduction abnormalities, arrhythmias, and heart failure. We present a case of a patient with advanced Fabry cardiomyopathy, in whom a small LV apical aneurysm was incidentally discovered on abdominal imaging, which could have easily evaded detection on standard transthoracic echocardiography. The LV apex should be thoroughly interrogated in patients with Fabry cardiomyopathy, as the finding of LV aneurysm could have important management implications with respect to the prevention of stroke and sudden cardiac death. [ABSTRACT FROM AUTHOR]

Heterozygous pathogenic variants in CIC, which encodes a transcriptional repressor, have been identified in individuals with neurodevelopmental phenotypes. To date, 11 CIC variants have been associated with the CIC‐related neurodevelopmental syndrome. Here, we describe three novel and one previously reported CIC variants in four individuals with neurodevelopmental delay. Notably, we report for the first time a de novo frameshift variant specific to the long isoform of CIC (CIC‐L, NM_001304815.1:c.1100dup, p.Pro368AlafsTer16) in an individual with speech delay, intellectual disability, and autism spectrum disorder. Our investigation into the function of CIC‐L reveals that partial loss of CIC‐L leads to transcriptional derepression of CIC target genes. We also describe a missense variant (NM_015125.3:c.683G>A, p.Arg228Gln) in an individual with a history of speech delay and relapsed pre‐B acute lymphoblastic leukemia. Functional studies of this variant suggest a partial loss of CIC transcriptional repressor activity. Our study expands the list of CIC pathogenic variants and contributes to the accumulating evidence that CIC haploinsufficiency or partial loss of function is a pathogenic mechanism causing neurodevelopmental phenotypes. [ABSTRACT FROM AUTHOR]

Background: The diagnostic journey for many rare disease patients remains challenging despite use of latest genetic technological advancements. We hypothesize that some patients remain undiagnosed due to more complex diagnostic scenarios that are currently not considered in genome analysis pipelines. To better understand this, we characterized the rare disorder (RD) spectrum using various bioinformatics resources (e.g., Orphanet/Orphadata, Human Phenotype Ontology, Reactome pathways) combined with custom-made R scripts.Results: Our in silico characterization led to identification of 145 borderline-common, 412 rare and 2967 ultra-rare disorders. Based on these findings and point prevalence, we would expect that approximately 6.53%, 0.34%, and 0.30% of individuals in a randomly selected population have a borderline-common, rare, and ultra-rare disorder, respectively (equaling to 1 RD patient in 14 people). Importantly, our analyses revealed that (1) a higher proportion of borderline-common disorders were caused by multiple gene defects and/or other factors compared with the rare and ultra-rare disorders, (2) the phenotypic expressivity was more variable for the borderline-common disorders than for the rarer disorders, and (3) unique clinical characteristics were observed across the disorder categories forming the spectrum.Conclusions: Recognizing that RD patients who remain unsolved even after genome sequencing might belong to the more common end of the RD spectrum support the usage of computational pipelines that account for more complex genetic and phenotypic scenarios. [ABSTRACT FROM AUTHOR]

B-cell lymphoma/leukemia 11B (BCL11B) is a C2H2 zinc finger transcription factor that is critically important for regulating the development and function of a variety of systems including the central nervous system, the skin, and the immune system. Germline heterozygous variants are associated with a spectrum of clinical disorders, including severe combined immunodeficiency as well as neurological, craniofacial, and dermal defects. Of these individuals, ~50% present with severe allergic disease. Here, we report the detailed clinical and laboratory workup of one of the most severe BCL11B-dependent atopic cases to date. Leveraging a zebrafish model, we were able to confirm a strong T-cell defect in the patient. Based on these data, we classify germline BCL11B-dependent atopic disease as a novel primary atopic disorder. [ABSTRACT FROM AUTHOR]

Monoamine neurotransmitter disorders present predominantly with neurologic features, including dystonic or dyskinetic cerebral palsy and movement disorders. Genetic conditions that lead to secondary defects in the synthesis, catabolism, transport, and metabolism of biogenic amines can lead to neurotransmitter abnormalities, which can present with similar features. Eleven patients with secondary neurotransmitter abnormalities were enrolled between 2011 and 2015. All patients underwent research-based whole exome and/or whole genome sequencing (WES/WGS). A trial of treatment with levodopa/carbidopa and 5-hydroxytryptophan was initiated. In six families with abnormal neurotransmitter profiles and neurological phenotypes, variants in known disease-causing genes (KCNJ6, SCN2A, CSTB in 2 siblings, NRNX1, KIF1A and PAK3) were identified, while one patient had a variant of uncertain significance in a candidate gene (DLG4) that may explain her phenotype. In 3 patients, no compelling candidate genes were identified. A trial of neurotransmitter replacement therapy led to improvement in motor and behavioral symptoms in all but two patients. The patient with KCNJ6 variant did not respond to L-dopa therapy, but rather experienced increased dyskinetic movements even at low dose of medication. The patient's symptoms harboring the NRNX1 deletion remained unaltered. This study demonstrates the utility of genome-wide sequencing in further understanding the etiology and pathophysiology of neurometabolic conditions, and the potential of secondary neurotransmitter deficiencies to serve as novel therapeutic targets. As there was a largely favorable response to therapy in our case series, a careful trial of neurotransmitter replacement therapy should be considered in patients with cerebrospinal fluid (CSF) monoamines below reference range. [ABSTRACT FROM AUTHOR]

Mosaic KRAS variants and other RASopathy genes cause oculoectodermal, encephalo‐cranio‐cutaneous lipomatosis, and Schimmelpenning‐Feuerstein‐Mims syndromes, and a spectrum of vascular malformations, overgrowth and other associated anomalies, the latter of which are only recently being characterized. We describe eight individuals in total (six unreported cases and two previously reported cases) with somatic KRAS variants and variably associated features. Given the findings of somatic overgrowth (in seven individuals) and vascular or lymphatic malformations (in eight individuals), we suggest mosaic RASopathies (mosaic KRAS variants) be considered in the differential diagnosis for individuals presenting with asymmetric overgrowth and lymphatic or vascular anomalies. We expand the association with embryonal tumors, including the third report of embryonal rhabdomyosarcoma, as well as novel findings of Wilms tumor and nephroblastomatosis in two individuals. Rare or novel findings in our series include the presence of epilepsy, polycystic kidneys, and T‐cell deficiency in one individual, and multifocal lytic bone lesions in two individuals. Finally, we describe the first use of targeted therapy with a MEK inhibitor for an individual with a mosaic KRAS variant. The purposes of this report are to expand the phenotypic spectrum of mosaic KRAS‐related disorders, and to propose possible mechanisms of pathogenesis, and surveillance of its associated findings. [ABSTRACT FROM AUTHOR]

Congenital uterine anomalies (CUA) may have major impacts on the health and social well‐being of affected individuals. Their expressivity is variable, with the most severe end of the spectrum being the absence of any fully or unilaterally developed uterus (aplastic uterus), which is a major feature in Mayer‐Rokitansky‐Kuster‐Hauser syndrome (MRKH). So far, etiologies of CUA remain largely unknown. As reports of familial occurrences argue for strong genetic contributors in some cases, we performed whole exome sequencing in nine multiplex families with recurrence of uterine and kidney malformations, a condition called hereditary urogenital adysplasia. Heterozygous likely causative variants in the gene GREB1L were identified in four of these families, confirming GREB1L as an important gene for proper uterine and kidney development. The apparent mode of inheritance was autosomal dominant with incomplete penetrance. The four families included fetuses with uterovaginal aplasia and bilateral renal agenesis, highlighting the importance to investigate GREB1L in such phenotypes. Subsequent sequencing of the gene in a cohort of 68 individuals with MRKH syndrome or uterine malformation (mostly sporadic cases) identified six additional variants of unknown significance. We therefore conclude that heterozygous GREB1L variants contribute to MRKH syndrome and this probably requires additional genetic or environmental factors for full penetrance. [ABSTRACT FROM AUTHOR]

Renpenning syndrome (OMIM: 309500) is a rare X‐linked disorder that causes intellectual disability, microcephaly, short stature, a variety of eye anomalies, and characteristic craniofacial features. This condition results from pathogenic variation of PQBP1, a polyglutamine‐binding protein involved in transcription and pre‐mRNA splicing. Renpenning syndrome has only been reported in affected males. Carrier females do not usually have clinical features, and in reported families with Renpenning syndrome, most female carriers exhibit favorable skewing of X‐chromosome inactivation. We describe a female with syndromic features typical of Renpenning syndrome. She was identified by exome sequencing to have a de novo heterozygous c.459_462delAGAG mutation in PQBP1 (Xp11.23), affecting the AG hexamer in exon 4, which is the most common causative mutation in this syndrome. Streaky hypopigmentation of the skin was observed, supporting a hypothesized presence of an actively expressed, PQBP1 mutation‐bearing X‐chromosome in some cells. X‐inactivation studies on peripheral blood cells demonstrated complete skewing in both the proband and her mother with preferential inactivation of the maternal X chromosome in the child. We demonstrated expression of the PQBP1 mutant transcript in leukocytes of the affected girl. Therefore, it is highly likely that the PQBP1 mutation arose from the paternal X chromosome. [ABSTRACT FROM AUTHOR]

Genetic disorders are one of the leading causes of infant mortality and are frequent in neonatal intensive care units (NICUs). Rapid genome-wide sequencing (GWS; whole genome or exome sequencing (ES)), due to its diagnostic capabilities and immediate impacts on medical management, is becoming an appealing testing option in the NICU setting. RAPIDOMICS was a trio-based rapid ES pilot study of 25 babies with suspected genetic disorders in the BC Women's Hospital NICU. ES and bioinformatic analysis were performed after careful patient ascertainment. Trio analysis was performed using an in-house pipeline reporting variants in known disease-causing genes. Variants interpreted by the research team as definitely or possibly causal of the infant's phenotype were Sanger validated in a clinical laboratory. The average time to preliminary diagnosis was 7.2 days. Sanger validation was pursued in 15 patients for 13 autosomal dominant and 2 autosomal recessive disorders, with an overall diagnostic rate (partial or complete) of 60%.Conclusion: In total, 72% of patients enrolled had a genomic diagnosis achieved through ES, multi-gene panel testing or chromosomal microarray analysis. Among these, there was an 83% rate of significant and immediate impact on medical decision-making directly related to new knowledge of the diagnosis. Health service implementation challenges and successes are discussed. What is Known: • Rapid genome-wide sequencing in the neonatal intensive care setting has a greater diagnostic hit rate and impact on medical management than conventional genetic testing. However, the impact of consultation with genetics and patient ascertainment requires further investigation. What is New: • This study demonstrates the importance of genetic consultation and careful patient selection prior to pursuing exome sequencing (ES). • In total, 15/25 (60%) patients achieved a diagnosis through ES and 18/25 (72%) through ES, multi-gene panel testing or chromosomal microarray analysis with 83% of those having immediate effects on medical management. [ABSTRACT FROM AUTHOR]

Highlights from the article: Keywords: Multiple intestinal atresia; combined immunodeficiency; TTC7A; VEOIBD In our patient, we demonstrate two novel deletions within I TTC7A i including a multi-exonic heterozygous deletion (exon 12-15) and a trans-allelic exon 15 deletion giving rise to MIA-CID complicated by very early onset inflammatory bowel disease and death in the first year of life. The patient's overlap panel (g) demonstrates complete absence of TTC7A (h) expression with retained beta-catenin expression (i), confirming TTC7A null expression status The patient was therefore compound heterozygous for two different deletions, which overlapped in exon 15, leading to homozygous deletion of exon 15 in the patient.

Increased application of next generation sequencing has led to the discovery of a multitude of new neurodevelopmental syndromes, contributing to an increased diagnostic rate for exome sequencing from 25% originally to 40% currently. Owing to the recent recognition of these syndromes, as well as the types of large‐scale studies (with limited phenotype information) often making these discoveries, these disorders may be poorly characterized clinically. As a result there is very limited information and disorder‐specific support available to patients and families. We used a qualitative approach to explore how families experience a diagnosis of a new syndrome. We conducted semi‐structured telephone interviews with parents and adult siblings of children who received a diagnosis of a new syndrome after whole exome sequencing (WES) performed through a translational research study. The interviews were recorded, transcribed verbatim, and transcripts were analyzed using grounded theory methods. Analysis of the 12 interviews revealed that a lack of information about the child's condition continues to play a large role in these families' experiences even after diagnosis. Almost all (92%) participants expressed ongoing uncertainty about their child's health and future. Most (83%) participants were interested in identifying other families with the same syndrome, which was related to both social support and seeking of information. Interestingly, 33% of participants worried about the child's risk for cancer due to their syndrome. Our results highlight some of the needs of families of children with new syndromes, and emphasize important issues care providers should address in pre‐ and post‐test genetic counseling for WES and whole genome sequencing. [ABSTRACT FROM AUTHOR]

NBEA is a candidate gene for autism, and de novo variants have been reported in neurodevelopmental disease (NDD) cohorts. However, NBEA has not been rigorously evaluated as a disease gene, and associated phenotypes have not been delineated. We identified 24 de novo NBEA variants in patients with NDD, establishing NBEA as an NDD gene. Most patients had epilepsy with onset in the first few years of life, often characterized by generalized seizure types, including myoclonic and atonic seizures. Our data show a broader phenotypic spectrum than previously described, including a myoclonic-astatic epilepsy-like phenotype in a subset of patients. Ann Neurol 2018;84:796-803. [ABSTRACT FROM AUTHOR]

Abstract: The role of disturbed chromatin remodeling in the pathogenesis of intellectual disability (ID) is well established and illustrated by de novo mutations found in a plethora of genes encoding for proteins of the epigenetic regulatory machinery. We describe mutations in the “SET nuclear proto‐oncogene” (SET), encoding a component of the “inhibitor of histone acetyltransferases” (INHAT) complex, involved in transcriptional silencing. Using whole exome sequencing, four patients were identified with de novo mutations in the SET gene. Additionally, an affected mother and child were detected who carried a frameshift variant in SET. Four patients were found in literature. The de novo mutations in patients affected all four known SET mRNA transcripts. LoF mutations in SET are exceedingly rare in the normal population and, if present, affect only one transcript. The pivotal role of SET in neurogenesis is evident from in vitro and animal models. SET interacts with numerous proteins involved in histone modification, including proteins encoded by known autosomal dominant ID genes, that is, EP300, CREBBP, SETBP1, KMT2A, RAC1, and CTCF. Our study identifies SET as a new component of epigenetic regulatory modules underlying human cognitive disorders, and as a first member of the Nucleosome Assembly Protein (NAP) family implicated in ID. [ABSTRACT FROM AUTHOR]

Abstract: Background: Access to clinical diagnostic genome‐wide sequencing (GWS; exome or whole genome sequencing) is limited in British Columbia. The establishment of a translational research initiative (CAUSES) to provide diagnostic genome‐wide sequencing for 500 children necessitated the development of a genomic consultation service, a clinical service established to provide consultation for physicians considering GWS for their pediatric patients throughout British Columbia. The Genomic Consultation Service provides patient‐specific genomic advice that may include: GWS, multi‐gene panel, single gene test, referral to medical genetics for clinical evaluation, or no genetic testing. Here, we describe and evaluate this service. Methods: We analyzed referral patterns, patient demographics, clinical indications, and genomic advice provided during the first year of this service. Comparison of outcomes from the first 6 months versus the last 6 months was performed. Results: A total of 407 referrals (238 males and 169 females [p = .0006]) were processed in the first year. Only children were eligible for referral and average patient age was 8 years. Medical genetics was the most frequent referring discipline, followed by biochemical disease and pediatric neurology, respectively. Most patients (68%) had syndromic intellectual disability. There was a significant difference in the frequency of referrals not appropriate for GWS in the first versus the second 6 months of the service (75/220 vs. 42/187; p = .01) suggesting increasing awareness of testing criteria by referring physicians. Conclusion: This triage service is utilized throughout the province and appears to be an important factor in the high diagnostic rate (>40%) achieved in our GWS program. [ABSTRACT FROM AUTHOR]

The forkhead box (FOX) transcription factors have roles in development, carcinogenesis, metabolism, and immunity. In humans FOXP1 mutations have been associated with language and speech defects, intellectual disability, autism spectrum disorder, facial dysmorphisms, and congenital anomalies of the kidney and urinary tract. In mice, Foxp1 plays critical roles in development of the spinal motor neurons, lymphocytes, cardiomyocytes, foregut, and skeleton. We hypothesized therefore that mutations of FOXP1 affect additional tissues in some humans. Supporting this hypothesis, we describe two individuals with novel variants of FOXP1 (NM_032682.5:c.975-2A>C and NM_032682.5:c.1574G>A) and additional features. One had a lung disease resembling neuroendocrine cell hyperplasia of infancy (NEHI), and the second had a skeletal disorder with undertubulation of the long bones and relapsing-remitting fevers associated with flushing and edema. Although attribution of these traits to mutation of FOXP1 requires ascertainment of additional patients, we hypothesize that the variable expression of these additional features might arise by means of stochastic developmental variation. [ABSTRACT FROM AUTHOR]

A 41-year-old Asian woman with bilateral renal angiomyolipomas (AML) was incidentally identified to have a balanced translocation, 46,XX,t(11; 12)(p15.4;q 15). She had no other features or family history to suggest a diagnosis of tuberous sclerosis. Her healthy daughter had the same translocation and no renal AML at the age of 3 years. Whole-genome sequencing was performed on genomic maternal DNA isolated from blood. A targeted de novo assembly was then conducted with ABySS for chromosomes 11 and 12. Sanger sequencing was used to validate the translocation breakpoints. As a result, genomic characterization of chromosomes 11 and 12 revealed that the 11 p breakpoint disrupted the NUP98 gene in intron 1, causing a separation of the promoter and transcription start site from the rest of the gene. The translocation breakpoint on chromosome 12q was located in a gene desert. NUP98 has not yet been associated with renal AML pathogenesis, but somatic NUP98 alterations are recurrently implicated in hematological malignancies, most often following a gene fusion event. We also found evidence for complex structural events involving chromosome 12, which appear to disrupt the TDG gene. We identified a TDGP1 partially processed pseudogene at 12p 12.1, which adds complexity to the de novo assembly. In conclusion, this is the first report of a germline constitutional structural chromosome rearrangement disrupting NUP98 that occurred in a generally healthy woman with bilateral renal AML. [ABSTRACT FROM AUTHOR]

Patients' perceptions of inconclusive results have been previously investigated in cancer genetics. The differences in how patients recall and interpret an uninformative test result compared to a known pathogenic result can affect medical decisions post disclosure. However, there is little to no data available on patients' interpretation and perception of uninformative genetic results in inherited heart disease. We report the results of a qualitative analysis of 16 telephone interviews with participants who received a negative or a variant of unknown significance (VUS) result from Long QT syndrome (LQTS) genetic testing. Our results suggest that the type of result (negative versus VUS) does not affect recall, regardless of the reason for testing. When receiving a negative result, a majority of participants appropriately perceived no change in their diagnosis, while the perception of risk for family members varied. The majority of participants felt they maintained an awareness of their condition after the result disclosure, and that clinical follow-up was similar to that planned prior to the genetic test result. Further work is needed to determine if there are any differences between obtaining a VUS result versus a negative result in this population. [ABSTRACT FROM AUTHOR]

Cardiac ion channelopathies are an important cause of sudden death in the young and include long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, and short QT syndrome. Genes that encode ion channels have been implicated in all of these conditions, leading to the widespread implementation of genetic testing for suspected channelopathies. Over the past half-century, researchers have also identified systemic pathologies that extend beyond the arrhythmic phenotype in patients with ion channel gene mutations, including deafness, epilepsy, cardiomyopathy, periodic paralysis, and congenital heart disease. A coexisting phenotype, such as cardiomyopathy, can influence evaluation and management. However, prior to recent molecular advances, our understanding and recognition of these overlapping phenotypes were poor. This review highlights the systemic and structural heart manifestations of the cardiac ion channelopathies, including their phenotypic spectrum and molecular basis. [ABSTRACT FROM AUTHOR]

Psychiatric genetic counseling (PGC) is an emerging specialty discipline within the genetic counseling profession. A specialist PGC service was founded in 2012 in Vancouver, Canada, and though patient benefits have been demonstrated, many physicians do not regularly refer patients to the service despite awareness of its availability. We conducted a qualitative study involving semi-structured telephone interviews with Vancouver-based physicians who were aware of the PGC service to explore this phenomenon. Interviews were audio-recorded, transcribed verbatim, coded, and analysed for emergent themes. Consistent with a grounded theory approach, constant comparison was employed throughout data collection and analysis. Analyses of interviews conducted with 12 physicians revealed that referral practices were informed by perceptions about the purpose of PGC and interpretation of patient cues. Physicians perceived PGC as an information-focused intervention, and considered referral when patients explicitly expressed desire for information about recurrence risk or etiology that they felt unable to adequately address themselves. Even when physicians identified psychotherapeutic benefits of PGC, patient needs of this nature were not perceived as cues prompting referral to PGC. These data suggest that further work is necessary to position PGC in physicians' minds as a service that could potentially benefit most individuals with psychiatric disorders and their families, and that it encompasses more than information provision. It is important to increase physicians' awareness of the complementary role that genetic counselors can play to that of the physician in providing psychotherapeutically oriented counselling about illness etiology. [ABSTRACT FROM AUTHOR]

Ranging from aplastic uterus (including Mayer-Rokitansky-Kuster-Hauser syndrome) to incomplete septate uterus, uterine malformations as a group are relatively frequent in the general population. Specific causes remain largely unknown. Although most occurrences ostensibly seem sporadic, familial recurrences have been observed, which strongly implicate genetic factors. Through the study of animal models, human syndromes, and structural chromosomal variation, several candidate genes have been proposed and subsequently tested with targeted methods in series of individuals with isolated, non-isolated, or syndromic uterine malformations. To date, a few genes have garnered strong evidence of causality, mainly in syndromic presentations ( HNF1B, WNT4, WNT7A, HOXA13). Sequencing of candidate genes in series of individuals with isolated uterine abnormalities has been able to suggest an association for several genes, but confirmation of a strong causative effect is still lacking for the majority of them. We review the current state of knowledge about the developmental origins of uterine malformations, with a focus on the genetic variants that have been implicated or associated with these conditions in humans, and we discuss potential reasons for the high rate of negative results. The evidence for various environmental and epigenetic factors is also reviewed. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: Mutations of TCF4, which encodes a basic helix-loop-helix transcription factor, cause Pitt-Hopkins syndrome (PTHS) via multiple genetic mechanisms. TCF4 is a complex locus expressing multiple transcripts by alternative splicing and use of multiple promoters. To address the relationship between mutation of these transcripts and phenotype, we report a three-generation family segregating mild intellectual disability with a chromosomal translocation disrupting TCF4.Results: Using whole genome sequencing, we detected a complex unbalanced karyotype disrupting TCF4 (46,XY,del(14)(q23.3q23.3)del(18)(q21.2q21.2)del(18)(q21.2q21.2)inv(18)(q21.2q21.2)t(14;18)(q23.3;q21.2)(14pter®14q23.3::18q21.2®18q21.2::18q21.1®18qter;18pter®18q21.2::14q23.3®14qter). Subsequent transcriptome sequencing, qRT-PCR and nCounter analyses revealed that cultured skin fibroblasts and peripheral blood had normal expression of genes along chromosomes 14 or 18 and no marked changes in expression of genes other than TCF4. Affected individuals had 12-33 fold higher mRNA levels of TCF4 than did unaffected controls or individuals with PTHS. Although the derivative chromosome generated a PLEKHG3-TCF4 fusion transcript, the increased levels of TCF4 mRNA arose from transcript variants originating distal to the translocation breakpoint, not from the fusion transcript.Conclusions: Although validation in additional patients is required, our findings suggest that the dysmorphic features and severe intellectual disability characteristic of PTHS are partially rescued by overexpression of those short TCF4 transcripts encoding a nuclear localization signal, a transcription activation domain, and the basic helix-loop-helix domain. [ABSTRACT FROM AUTHOR]

Introduction: Tracheobronchomegaly (Mounier-Kuhn Syndrome) is a rare disease characterized by tracheal enlargement and associated loss of elastic fibers in the trachea and main bronchi. Materials: MEDLINE, Index Medicus, and other databases were searched with pre-defined criteria to identify cases of tracheobronchomegaly (TBM). Two new cases of TBM were also identified from the Provincial Medical Genetics Program of British Columbia. Results: We identified 166 publications describing 365 occurrences of TBM. We observed that affected individuals could be grouped into subgroups according to clinical features. Type 1A (105 individuals) consists of infants who developed TBM after having undergone fetoscopic tracheal occlusion, and Type 1B patients (24 individuals) are infants and children who developed TBM after prolonged intubation. Type 2 individuals developed TBM following recurrent pulmonary infections (2A) (14 individuals) or pulmonary fibrosis (2B) (10 individuals). Type 3 represents TBM with evidence of extra-pulmonary elastolysis (18 individuals), and Type 4 denotes the development of TBM with no clear predisposing factors (196 individuals). Both of our patients had TBM and evidence of extra-pulmonary elastolysis. As well, one patient had a mildly dilated aortic root, which is a previously unreported co-occurrence. Conclusion: We introduce a novel classification scheme, which may sort patients into etiologically distinct groups, furthering our understanding of its pathogenesis and potentially, prevention or therapy. We also hypothesize that TBM and generalized elastolysis may have etiological commonalities, suggesting a need for further study. [ABSTRACT FROM AUTHOR]

Adams-Oliver syndrome (AOS) is a rare malformation syndrome characterized by the presence of two anomalies: aplasia cutis congenita of the scalp and transverse terminal limb defects. Many affected individuals also have additional malformations, including a variety of intracranial anomalies such as periventricular calcification in keeping with cerebrovascular microbleeds, impaired neuronal migration, epilepsy, and microcephaly. Cardiac malformations can be present, as can vascular dysfunction in the forms of cutis marmorata telangiectasia congenita, pulmonary vein stenoses, and abnormal hepatic microvasculature. Elucidated genetic causes include four genes in different pathways, leading to a model of AOS as a multi-pathway disorder. We identified an infant with mild aplasia cutis congenita and terminal transverse limb defects, developmental delay and a severe, diffuse angiopathy with incomplete microvascularization. Whole-genome sequencing documented two rare truncating variants in DOCK6, a gene associated with a type of autosomal recessive AOS that recurrently features periventricular calcification and impaired neurodevelopment. We highlight an unexpectedly high frequency of likely deleterious mutations in this gene in the general population, relative to the rarity of the disease, and discuss possible explanations for this discrepancy. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Introduction: Cleft lip with or without palate (CLP) can be diagnosed antenatally through ultrasound, and may be categorised as apparently isolated versus associated with other malformations. Limited data exist on the long-term outcomes following antenatal diagnosis of apparently isolated CLP. Aim: This study examined the long-term post-natal outcomes of CLP when found in isolation antenatally, in order to determine the rates of unexpected additional anomalies, developmental delay or genetic syndromes. Patients and methods: A retrospective chart review of antenatal and post-natal medical charts was completed for a ten-year period between January 2000 and December 2009. At least 2 years of available post-natal clinical information was required for inclusion in the study. Results: A total of 97 cases of antenatally isolated CLP were ascertained. Fifteen pregnancies were terminated. Follow-up data were available for 81 liveborns, though 4 were lost to follow-up prior to 2 years of age. Twelve of the 77 children meeting study criteria were identified to have other major malformations and/or developmental disability either later in the pregnancy or post-natally. Findings included familial clefting syndromes, trisomy 21, autism spectrum disorders, brain malformations, fetal alcohol syndrome and Kabuki syndrome, among other findings. Another 11 children had additional anomalies of minor impact. Examples of findings include a perimembranous ventricular septal defect, mild unilateral optic nerve hypoplasia, mild pulmonary artery stenosis with a small atrial septal defect, and transient delays in fine and gross motor skills. No children with clefting of the lip only had major additional diagnoses. Conclusions: The frequency of an associated complex developmental disorder following an otherwise reassuring fetal ultrasound is around 15%. A few diagnoses could be suspected at the antenatal assessment based on family history or exposures. Our study is lacking comprehensive assessment on the yield of genomic microarray testing for this population. [ABSTRACT FROM AUTHOR]

Glycosphingolipids are ubiquitous constituents of eukaryotic plasma membranes, and their sialylated derivatives, gangliosides, are the major class of glycoconjugates expressed by neurons. Deficiencies in their catabolic pathways give rise to a large and well-studied group of inherited disorders, the lysosomal storage diseases. Although many glycosphingolipid catabolic defects have been defined, only one proven inherited disease arising from a defect in ganglioside biosynthesis is known. This disease, because of defects in the first step of ganglioside biosynthesis (GM3 synthase), results in a severe epileptic disorder found at high frequency amongst the Old Order Amish. Here we investigated an unusual neurodegenerative phenotype, most commonly classified as a complex form of hereditary spastic paraplegia, present in families from Kuwait, Italy and the Old Order Amish. Our genetic studies identified mutations in B4GALNT1 (GM2 synthase), encoding the enzyme that catalyzes the second step in complex ganglioside biosynthesis, as the cause of this neurodegenerative phenotype. Biochemical profiling of glycosphingolipid biosynthesis confirmed a lack of GM2 in affected subjects in association with a predictable increase in levels of its precursor, GM3, a finding that will greatly facilitate diagnosis of this condition. With the description of two neurological human diseases involving defects in two sequentially acting enzymes in ganglioside biosynthesis, there is the real possibility that a previously unidentified family of ganglioside deficiency diseases exist. The study of patients and animal models of these disorders will pave the way for a greater understanding of the role gangliosides play in neuronal structure and function and provide insights into the development of effective treatment therapies. [ABSTRACT FROM AUTHOR]

Causal attributions control, beliefs, and helpful and unhelpful support attempts were examined among people experiencing chronic fatigue syndrome (CFS) and their close others. Results revealed that 84% of respondents with CFS believed that their illness was due, at least in part, to physical or external causes, whereas 47% mentioned internal/psychological causes. Reports of internal causal attributions for CFS were positively correlated with indicators of poor psychological adjustment among those with CFS. Having an external locus of control (i.e., to powerful others) was also associated with poorer psychological adjustment among respondents with CFS. Close others' causal attributions to internal factors were related to frequency of self-reported unhelpful support attempts and to reports of depression and anxiety those respondents with CFS. [ABSTRACT FROM AUTHOR]

Proteolytic processing of the β-amyloid precursor protein (APP) at the β site is essential to generate Aβ. BACE1, the major β-secretase involved in cleaving APP, has been identified as a type 1 membrane-associated aspartyl protease. We have cloned a 2.1-kb fragment upstream of the human BACE1 gene and identified key regions necessary for promoter activity. BACE1 gene expression is controlled by a TATA-less promoter. The region of bp -619 to +46 is the minimal promoter to control the transcription of the BACE1 gene. Several putative cis-acting elements, such as a GC box, HSF-1, a PU box, AP1, AP2, and lymphokine response element, are found in the 5' flanking region of the BACE1 gene. Transcriptional activation and gel shift assays demonstrated that the BACE1 promoter contains a functional Sp1 response element, and overexpression of the transcription factor Sp1 potentiates BACE gene expression and APP processing to generate Aβ. Furthermore, Sp1 knockout reduced BACE1 expression. These results suggest that BACE1 gene expression is tightly regulated at the transcriptional level and that the transcription factor Sp1 plays an important role in regulation of BACE1 to process APP generating Aβ in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background:Cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy with mitomycin C for peritoneal carcinomatosis is used as a palliative treatment for a variety of malignancies. The purpose of this study was to measure the quality of life (QOL) of survivors (>3 years) after treatment. Methods:Patients were interviewed by telephone with the following tools: (1) the Functional Assessment of Cancer Therapy–Colon (FACT-C), (2) the Short Form of the Medical Outcomes Study Questionnaire, (3) the Center for Epidemiologic Studies–Depression scale, (4) the Life Appreciation scale, (5) the Psychosocial Concerns Questionnaire, and (6) performance status rating. Results:Seventeen (10 appendix, 5 large intestine, 1 ovarian, and 1 peritoneum) of 109 patients were interviewed from 3.1 to 8.0 years after treatment. Ten patients (62.5%) described their health as excellent or very good. No limitations on moderate activity were reported in 94% of cases. Paired t-tests were used to compare 10 patients who had baseline QOL data. FACT mean difference scores and P values (positive difference scores indicate improved QOL) were functional well-being: 4.9, P = .01; physical well-being: 3.3, P = .05; and FACT total: 14.3, P = .02. Conclusions:Long-term survival with good QOL is possible for selected patients with peritoneal carcinomatosis after cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy. [ABSTRACT FROM AUTHOR]

We thank Compute Canada for the Research Allocation Competitions allocation, which facilitated our analysis of the IMAG INE and EGA genomes, and Julia Handra for coordinating the STR molecular testing of the clinical samples. Genome-wide sequencing as a first-tier screening test for short tandem repeat expansions. [Extracted from the article]