Craniofacial features of POLR3-related leukodystrophy caused by biallelic variants in POLR3A, POLR3B and POLR1C.

BACKGROUND: RNA polymerase III-related or 4H leukodystrophy (POLR3-HLD) is an autosomal recessive hypomyelinating leukodystrophy characterized by neurological dysfunction, hypodontia and hypogonadotropic hypogonadism. The disease is caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C or POLR3K. Craniofacial abnormalities reminiscent of Treacher Collins syndrome have been originally described in patients with POLR3-HLD caused by biallelic pathogenic variants in POLR1C. To date, no published studies have appraised in detail the craniofacial features of patients with POLR3-HLD. In this work, the specific craniofacial characteristics of patients with POLR3-HLD associated with biallelic pathogenic variants in POLR3A, POLR3B and POLR1C are described. METHODS: The craniofacial features of 31 patients with POLR3-HLD were evaluated, and potential genotype-phenotype associations were evaluated. RESULTS: Various craniofacial abnormalities were recognized in this patient cohort, with each individual presenting at least one craniofacial abnormality. The most frequently identified features included a flat midface (61.3%), a smooth philtrum (58.0%) and a pointed chin (51.6%). In patients with POLR3B biallelic variants, a thin upper lip was frequent. Craniofacial anomalies involving the forehead were most commonly associated with biallelic variants in POLR3A and POLR3B while a higher proportion of patients with POLR1C biallelic variants demonstrated bitemporal narrowing. CONCLUSION: Through this study, we demonstrated that craniofacial abnormalities are common in patients with POLR3-HLD. This report describes in detail the dysmorphic features of POLR3-HLD associated with biallelic variants in POLR3A, POLR3B and POLR1C.

Investigating genotype-to-phenotype correlation in CHARGE syndrome by deep phenotyping and multiparametric clustering.

CHARGE syndrome, due to CHD7 pathogenic variations, is an autosomal dominant disorder characterized by a large spectrum of severity. Despite the great number of variations reported, no clear genotype-to-phenotype correlation has been reported. Unsupervised machine learning and clustering was undertaken using a retrospective cohort of 42 patients, after deep radiologic and clinical phenotyping, to establish genotype-phenotype correlation for CHD7-related CHARGE syndrome. It resulted in three clusters showing phenotypes of different severities. While no clear genotype-phenotype correlation appeared within the first two clusters, a single patient was outlying the cohort data (cluster 3) with the most atypical phenotype and the most distal frameshift variant in the gene. We added two other patients with similar distal pathogenic variants and observed a tendency toward mild and/or atypical phenotypes. We hypothesized that this finding could potentially be related to escaping nonsense mediated RNA decay, but found no evidence of such decay in vivo for any of the CHD7 pathogenic variation tested. This indicates that this milder phenotype may rather result from the production of a protein retaining all functional domains.

A Cockayne-like phenotype resulting from a de novo variant in MORC2: expanding the phenotype of MORC2-related disorders.

Cockayne syndrome is a rare inherited DNA repair multisystemic disorder. Here, we aim to raise awareness of the phenotypic resemblances between Cockayne syndrome and the neurodevelopmental disorder caused by pathogenic variants in MORC2, a gene also involved in DNA repair. Using exome sequencing, we identified a de novo pathogenic variant in MORC2 in our patient. Our patient's phenotype was characterized by multiple features evocative of Cockayne syndrome. Based on our patient's phenotype, in addition to the phenotypic description of patients with pathogenic variants in MORC2 reported in the literature, we suggest that pathogenic variants in this gene are associated with a Cockayne-like phenotype.

The incidence and carrier frequency of Tay-Sachs disease in the French-Canadian population of Quebec based on retrospective data from 24 years, 1992-2015.

Tay-Sachs disease (TSD) is a hereditary neurodegenerative condition inherited through an autosomal recessive pattern. The incidence and carrier frequency of infantile TSD were found to be increased among French Canadians in specific areas of the province of Quebec or calculated from New England populations with French-Canadian heritage. No accurate infantile TSD carrier frequency for the whole French-Canadian population in Quebec has been published. In this study, we estimate the incidence and carrier frequency of infantile TSD in the Quebec French-Canadian population. The number of TSD cases was ascertained during the 1992-2015 period, as well as the number of births to mothers whose language of use is French. Seven cases of TSD have been diagnosed in Quebec during the period of ascertainment. This corresponds to an incidence of 1/218,144, which in turn corresponds to a carrier frequency of 1/234. In the same 24-year period, there are two French-Canadian couples who had a fetus prenatally diagnosed with TSD. If these cases are included, the incidence of TSD in the French-Canadian population of Quebec is 1/169,668 and the carrier frequency 1/206. These findings can be used for genetic counseling and policy decisions regarding carrier screening for TSD in populations of French-Canadian descent.

No. 380-Investigation and Management of Prenatally Identified Microcephaly.

OBJECTIVE: To update Canadian maternity care and reproductive health care providers on the diagnostic criteria of fetal microcephaly and provide information on the relevant investigations, prognosis, and pre- and perinatal management of this prenatal finding. INTENDED USERS: All maternity care (most responsible health provider [MRHP]) and pediatric providers; genetic counsellors; maternity nurses; nurse practitioners; provincial maternity care administrators; medical students; postgraduate residents, and fellows. OUTCOMES: To provide better counselling and appropriate clinical management to women and families who have received a prenatal diagnosis of fetal microcephaly. EVIDENCE: Published literature was retrieved through searches of PubMed or Medline, CINAHL, and The Cochrane Library in 2018, using appropriate key words (prenatal ultrasound, prenatal imaging, fetal, antenatal, or prenatal microcephaly). Additional publications were identified from the bibliographies of these articles. SEARCH PERIOD: Seven years (2010-2018); completed final search April 19, 2018. The primary author completed validation of the articles. BENEFITS, HARMS, AND COSTS: This document educates readers about (1) the diagnostic criteria for fetal microcephaly, (2) its potential etiologies, (3) investigation and management options both pre- and postnatally. It proposes an evidence-based approach to the diagnosis and management of prenatally detected microcephaly. These recommendations are based on expert opinion and have not been subjected to a health economics assessment. Local or provincial implementation will be required. The authors recognize that there is variability across Canada in access to the cited services and resources. As such, these recommendations were developed in an attempt to promote access and to provide guidance for all provinces and territories across the country. VALUES: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care.

No 380 - Évaluation et prise en charge de la microcéphalie détectée avant la naissance.

OBJECTIF: Informer les fournisseurs canadiens de soins de santé périnatale des critères diagnostiques de la microcéphalie fœtale et fournir l'information sur les analyses pertinentes, le pronostic, et la prise en charge prénatale et périnatale en lien avec a cette observation prénatale. DESTINATAIRES: Tous les fournisseurs de soins de maternité (fournisseurs principaux de soins de santé) et de soins de pédiatrie; les conseiller(e)s en génétique; les infirmièr(e)s en soins de maternité; les infirmièr(e)s practicien(ne)s, les administrateur(trice)s provinciaux de soins de maternité; les étudiant(e)s, en médecine; les résident(e)s postdoctoraux et les stagiaires (fellows). RéSULTATS: Fournir de meilleurs conseils et une prise en charge clinique adéquate aux femmes et aux familles qui ont reçu un diagnostic prénatal de microcéphalie fœtale. DONNéES PROBANTES: La documentation publiée est tirée de recherches effectuées en 2018 dans le moteur PubMed et les bases de données Medline, CINAHL et Cochrane Library au moyen de mots-clés anglais pertinents (prenatal ultrasound, prenatal imaging, fetal, antenatal ou prenatal microcephaly). Des publications supplémentaires ont été sélectionnées à partir des notices bibliographiques de ces articles. PéRIODE DE RECHERCHE: Sept ans (2010-2018); la dernière recherche a été effectuée le 19 avril 2018. L'auteur principal a terminé la validation des articles. AVANTAGES, PRéJUDICES ET COûTS: Le présent document renseigne les lecteurs au sujet (1) des critères diagnostiques de la microcéphalie fœtale, (2) de ses étiologies potentielles et (3) des analyses et options de prise en charge avant et après la naissance. Il propose une méthode fondée sur des données probantes pour établir le diagnostic et déterminer la prise en charge de la microcéphalie détectée avant la naissance. Ces recommandations sont fondées sur l'opinion d'experts, mais n'ont pas fait l'objet d'une évaluation économique de la santé. Une mise en œuvre aux échelles locale ou provinciale sera requise. Les auteurs reconnaissent que l'accès aux services et ressources mentionnés varie au Canada. Par conséquent, ces recommandations ont été formulées dans la perspective de promouvoir l'accès et de fournir une orientation pour toutes les provinces et tous les territoires du pays. CRITèRES: La solidité des données probantes indiquées s'appuie sur les critères décrits dans le rapport du Groupe d'étude canadien sur les soins de santé préventifs. RECOMMANDATIONS.

GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects.

BACKGROUND: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. METHODS: Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. RESULTS: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. CONCLUSIONS: In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.

No. 363-Investigation and Management of Non-immune Fetal Hydrops.

OBJECTIVE: To describe the current investigation and management of non-immune fetal hydrops with a focus on treatable or recurring etiologies. OUTCOMES: To provide better counselling and management in cases of prenatally diagnosed non-immune hydrops. EVIDENCE: Published literature was retrieved through searches of PubMed or MEDLINE, CINAHL, and The Cochrane Library in 2017 using key words (non-immune hydrops fetalis, fetal hydrops, fetal therapy, fetal metabolism). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, observational studies, and significant case reports. Additional publications were identified from the bibliographies of these articles. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to September 2017. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinicalpractice guideline collections, clinical trial registries, and national and international medical specialty societies. BENEFITS, HARMS, AND COSTS: These guidelines educate readers about the causes of non-immune fetal hydrops and its prenatal counselling and management. It also provides a standardized approach to non-immune fetal hydrops, emphasizing the search for prenatally treatable conditions and recurrent genetic etiologies. VALUES: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care.

N° 363 - Évaluation et prise en charge de l'anasarque fœtoplacentaire non immune.

OBJECTIF: Décrire les méthodes actuelles d'évaluation et de prise en charge de l'anasarque fœtoplacentaire non immune en mettant l'accent sur les étiologies traitables ou récurrentes. RéSULTATS: Offrir de meilleurs services de conseil et de prise en charge en cas d'anasarque fœtoplacentaire non immune diagnostiquée en période prénatale. DONNéES: La littérature publiée a été récupérée au moyen de recherches menées dans PubMed, MEDLINE, CINAHL, et la Bibliothèque Cochrane en 2017 à l'aide de mots-clés (« non-immune hydrops fetalis ¼, « fetal hydrops ¼, « fetal therapy ¼, « fetal metabolism ¼). Les articles retenus portaient sur des revues systématiques, des essais cliniques contrôlés, randomisés ou non, des études observationnelles et des études de cas importantes. D'autres publications ont été repérées dans les bibliographies de ces articles. Aucune restriction de date ou de langue n'a été employée. Les recherches ont été mis à jour régulièrement, et les résultats ont été incorporés à la directive clinique jusqu'en septembre 2017. Nous avons également tenu compte de la littérature grise (non publiée) trouvée sur les sites Web d'organismes d'évaluation des technologies de la santé et d'autres organismes liés aux technologies de la santé, dans des collections de directives cliniques et des registres d'essais cliniques, et obtenue auprès d'associations nationales et internationales de médecins spécialistes. AVANTAGES, INCONVéNIENTS ET COûTS: La présente directive clinique renseigne les lecteurs sur les causes de l'anasarque fœtoplacentaire non immune ainsi que sur son évaluation et sa prise en charge. Elle propose également une approche standardisée d'évaluation et de prise en charge, et met l'accent sur la recherche des conditions traitables en période prénatale et des étiologies génétiques récurrentes. VALEURS: La qualité des données probantes a été évaluée en fonction des critères décrits dans le rapport du Groupe d'étude canadien sur les soins de santé préventifs. RECOMMANDATIONS.

No. 365-Fetal and Perinatal Autopsy in Prenatally Diagnosed Fetal Abnormalities with Normal Chromosome Analysis.

OBJECTIVE: To review the information on fetal and perinatal autopsies, the process of obtaining consent, and the alternative information-gathering options following a prenatal diagnosis of non-chromosomal anomalies in order to assist health care providers in providing postnatal counselling regarding diagnosis and potential recurrence risks. OUTCOMES: To provide better counselling about fetal and perinatal autopsies for women and families who are dealing with a prenatally diagnosed non-chromosomal fetal anomaly. EVIDENCE: Published literature was retrieved through searches of PubMed or Medline, CINAHL, and The Cochrane Library in 2010, 2011, and 2017, using appropriate key words (fetal autopsy postmortem, autopsy, perinatal postmortem examination, autopsy protocol, postmortem magnetic resonance imaging, autopsy consent, tissue retention, autopsy evaluation). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. Additional publications were identified from the bibliographies of these articles. There were no date or language restrictions. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. BENEFITS, HARMS, AND COSTS: This update educates readers about (1) the benefits of a fetal perinatal autopsy, (2) the consent process, and (3) the alternatives when the family declines autopsy. It also highlights the need for a standardized approach to fetal and perinatal autopsies, emphasizing pertinent additional sampling when indicated. The authors recognize that there is variability across Canada in access to the cited services and resources. As such, these recommendations were developed in an attempt to promote access and to provide a minimum standard for all provinces and territories across the country. VALUES: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table).

N° 365 -Autopsies fœtales et périnatales en cas d'anomalies fœtales diagnostiquées avant la naissance avec une analyse chromosomique normale.

OBJECTIF: Examiner les données sur les autopsies fœtales et périnatales, le processus de consentement et les options de collecte de renseignements à la suite d'un diagnostic prénatal d'anomalies non chromosomiques afin d'aider les fournisseurs de soins à offrir du conseil postnatal au sujet du diagnostic et des éventuels risques de récurrence. RéSULTATS: Offrir de meilleurs conseils sur les autopsies fœtales et périnatales aux femmes et aux familles qui ont reçu un diagnostic prénatal d'anomalie fœtale non chromosomique. ÉVIDENCE: Nous avons examiné des études publiées récupérées au moyen de recherches dans PubMed, Medline, CINAHL et la Bibliothèque Cochrane en 2010, en 2011 et en 2017 à l'aide de mots-clés appropriés (« fetal autopsy postmortem ¼, « autopsy ¼, « perinatal postmortem examination ¼, « autopsy protocol ¼, « postmortem magnetic resonance imaging ¼, « autopsy consent ¼, « tissue retention ¼ et « autopsy evaluation ¼). Nous n'avons tenu compte que des résultats provenant de revues systématiques, d'essais cliniques, randomisés ou non, et d'études observationnelles. D'autres publications ont été repérées dans les bibliographies de ces articles. Aucune restriction de date ou de langue n'a été employée. Nous avons également tenu compte de la littérature grise (non publiée) trouvée sur les sites Web d'organismes d'évaluation des technologies de la santé et d'autres organismes liés aux technologies de la santé, dans des collections de directives cliniques et dans des registres d'essais cliniques, et obtenue auprès d'associations nationales et internationales de médecins spécialistes. AVANTAGES, DéSAVANTAGES ET COUTS: La présente mise à jour renseigne les lecteurs sur : 1) les avantages de l'autopsie fœtale ou périnatale; 2) le processus de consentement; et 3) les autres options offertes aux familles qui refusent l'autopsie. Elle met également en évidence la nécessité d'adopter une démarche normalisée pour la réalisation des autopsies fœtales et périnatales, et met l'accent sur les prélèvements additionnels qui peuvent être pertinents. Les auteurs sont conscients que l'accès aux ressources et aux services mentionnés varie d'un endroit l'autre au Canada; les recommandations formulées ont donc pour but de promouvoir l'accès et de fournir une norme minimale aux provinces et aux territoires du pays. VALEURS: La qualité des données a été évaluée au moyen des critères énoncés dans le rapport du Groupe d'étude canadien sur les soins de santé préventifs (tableau). RECOMMANDATIONS.

No. 348-Joint SOGC-CCMG Guideline: Update on Prenatal Screening for Fetal Aneuploidy, Fetal Anomalies, and Adverse Pregnancy Outcomes.

OBJECTIVE: To review the available prenatal screening options in light of the recent technical advances and to provide an update of previous guidelines in the field of prenatal screening. INTENDED USERS: Health care providers involved in prenatal screening, including general practitioners, obstetricians, midwives, maternal fetal medicine specialists, geneticists, and radiologists. TARGET POPULATION: All pregnant women receiving counselling and providing informed consent for prenatal screening. EVIDENCE: Published literature was retrieved through searches of Medline, PubMed, and the Cochrane Library in and prior to March 2016 using an appropriate controlled vocabulary (prenatal diagnosis, amniocentesis, chorionic villi sampling, non-invasive prenatal screening) and key words (prenatal screening, prenatal genetic counselling). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies written in English and published from January 1985 to May 2016. Searches were updated on a regular basis and incorporated in the guideline. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical speciality societies. GUIDELINE UPDATE: Evidence will be reviewed 5 years after publication to determine whether all or part of the guideline should be updated. However, if important new evidence is published prior to the 5-year cycle, the review process may be accelerated for a more rapid update of some recommendations.

Joint SOGC-CCMG Opinion for Reproductive Genetic Carrier Screening: An Update for All Canadian Providers of Maternity and Reproductive Healthcare in the Era of Direct-to-Consumer Testing.

OBJECTIVE: This guideline was written to update Canadian maternity care and reproductive healthcare providers on pre- and postconceptional reproductive carrier screening for women or couples who may be at risk of being carriers for autosomal recessive (AR), autosomal dominant (AD), or X-linked (XL) conditions, with risk of transmission to the fetus. Four previous SOGC- Canadian College of Medical Geneticists (CCMG) guidelines are updated and merged into the current document. INTENDED USERS: All maternity care (most responsible health provider [MRHP]) and paediatric providers; maternity nursing; nurse practitioner; provincial maternity care administrator; medical student; and postgraduate resident year 1-7. TARGET POPULATION: Fertile, sexually active females and their fertile, sexually active male partners who are either planning a pregnancy or are pregnant (preferably in the first trimester of pregnancy, but any gestational age is acceptable). OPTIONS: Women and their partners will be able to obtain appropriate genetic carrier screening information and possible diagnosis of AR, AD, or XL disorders (preferably pre-conception), thereby allowing an informed choice regarding genetic carrier screening and reproductive options (e.g., prenatal diagnosis, preimplantation genetic diagnosis, egg or sperm donation, or adoption). OUTCOMES: Informed reproductive decisions related to genetic carrier screening and reproductive outcomes based on family history, ethnic background, past obstetrical history, known carrier status, or genetic diagnosis. SOGC REPRODUCTIVE CARRIER SCREENING SUMMARY STATEMENT (2016): Pre-conception or prenatal education and counselling for reproductive carrier screening requires a discussion about testing within the three perinatal genetic carrier screening/diagnosis time periods, which include pre-conception, prenatal, and neonatal for conditions currently being screened for and diagnosed. This new information should be added to the standard reproductive carrier screening protocols that are already being utilized by the most responsible maternity provider through the informed consent process with the patient. (III-A; GRADE low/moderate) SOGC OVERVIEW OF RECOMMENDATIONS QUALITY AND GRADE: There was a strong observational/expert opinion (quality and grade) for the genetic carrier literature with randomized controlled trial evidence being available only for the invasive testing. Both the Canadian Task Force on Preventive Health Care quality and classification and the GRADE evidence quality and grade are provided. EVIDENCE: MEDLINE; PubMed; government neonatal screening websites; key words/common reproductive genetic carrier screened diseases/previous SOGC Guidelines/medical academic societies (Society of Maternal-Fetal Medicine [SMFM]; American College of Medical Genetics and Genomics; American College of Obstetricians and Gynecologists [ACOG]; CCMG; Royal College Obstetrics and Gynaecology [RCOG] [UK]; American Society of Human Genetics [ASHG]; International Society of Prenatal Diagnosis [ISPD])/provincial neonatal screening policies and programs; search terms (carrier screening, prenatal screening, neonatal genetic/metabolic screening, cystic fibrosis (CF), thalassemia, hemoglobinopathy, hemophilia, Fragile X syndrome (FXS), spinal muscular atrophy, Ashkenazi Jewish carrier screening, genetic carrier screening protocols, AR, AD, XL). SEARCH PERIOD: 10 years (June 2005-September 2015); initial search dates June 30, 2015 and September 15, 2015; completed final search January 4, 2016. Validation of articles was completed by primary authors RD Wilson and I De Bie. BENEFITS, HARMS, AND COST: Benefits are to provide an evidenced based reproductive genetic carrier screening update consensus based on international opinions and publications for the use of Canadian women, who are planning a pregnancy or who are pregnant and have been identified to be at risk (personal or male partner family or reproductive history) for the transmission of a clinically significant genetic condition to their offspring with associated morbidity and/or mortality. Harm may arise from having counselling and informed testing of the carrier status of the mother, their partner, or their fetus, as well as from declining to have this counselling and informed testing or from not having the opportunity for counselling and informed testing. Costs will ensue both from the provision of opportunities for counselling and testing, as well as when no such opportunities are offered or are declined and the birth of a child with a significant inherited condition and resulting morbidity/mortality occurs; these comprise not only the health care costs to the system but also the social/financial/psychological/emotional costs to the family. These recommendations are based on expert opinion and have not been subjected to a health economics assessment and local or provincial implementation will be required. GUIDELINE UPDATE: This guideline is an update of four previous joint SOGC-CCMG Genetic Screening Guidelines dated 2002, 2006, 2008, and 2008 developed by the SOGC Genetic Committee in collaboration with the CCMG Prenatal Diagnosis Committee (now Clinical Practice Committee). 2016 CARRIER SCREENING RECOMMENDATIONS.

A Review of the Clinical Features and Management of Systemic Congenital Mastocytosis through the Presentation of An Unusual Prenatal-Onset Case.

Mastocytosis is a heterogeneous group of rare hematological disorders that can occur in infancy. We report a 16-year-old girl who presented with an aggressive form of systemic congenital mastocytosis, associated with a significant global developmental delay, deafness, and multiple anomalies. At 4 years of age, she developed a germinoma presenting as an invasive spinal mass. Extensive cytogenetic, metabolic, and molecular genetic studies that included whole-exome sequencing studies revealed a KIT alteration (NM_000222.3(KIT):c2447A > 7 pAsp816Val) and likely pathogenic variant in the DNA from peripheral blood and skin lesions. C-kit was also found to be overexpressed in the spinal tumor cells. We compared the features of this child to those of six previously reported pediatric patients with cutaneous mastocytosis, microcephaly, microtia, and/or hearing loss reported in OMIM as mastocytosis, conductive hearing loss, and microtia (MIM 248910), for which the etiology has not yet been determined. This report extends the currently recognized spectrum of KIT-related disorders and provides clues as to the potential etiology of a syndromic form of congenital mastocytosis. International efforts to understand the benefits of long-term targeted therapy with tyrosine kinase inhibitors for this KIT-altered rare disease should continue to be evaluated in clinical trials.

Severe Antenatal Hypertrophic Cardiomyopathy Secondary to ACAD9-Related Mitochondrial Complex I Deficiency.

Introduction: Antenatal presentation of hypertrophic cardiomyopathy (HCM) is rare. We describe familial recurrence of antenatal HCM associated with intrauterine growth restriction and the diagnostic process undertaken. Methods: Two pregnancies with antenatal HCM were followed up. Biological assessment including metabolic analyses, genetic analyses, and respiratory chain study was performed. We describe the clinical course of these two pregnancies, antenatal manifestations as well as specific histopathological findings, and review the literature. Results: The assessment revealed a deficiency in complex I of the respiratory chain and two likely pathogenic variations in the ACAD9 gene. Discussion and Conclusion: Antenatal HCM is rare and a diagnosis is not always made. In pregnancies presenting with cardiomyopathy and intrauterine growth restriction, ACAD9 deficiency should be considered as one of the potential underlying diagnoses, and ACAD9 molecular testing should be included among other prenatal investigations.

Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway.

BACKGROUND: Since the first description of a BRWD3-associated nonsydromic intellectual disability (ID) disorder in 2007, 21 additional families have been reported in the literature. METHODS: Using exome sequencing (ES) and international data sharing, we identified 14 additional unrelated individuals with pathogenic BRWD3 variants (12 males and 2 females, including one with skewed X-inactivation). We reviewed the 31 previously published cases in the literature with clinical data available, and describe the collective phenotypes of 43 males and 2 females, with 33 different BRWD3 variants. RESULTS: The most common features in males (excluding one patient with a mosaic variant) included ID (39/39 males), speech delay (24/25 males), postnatal macrocephaly (28/35 males) with prominent forehead (18/25 males) and large ears (14/26 males), and obesity (12/27 males). Both females presented with macrocephaly, speech delay, and epilepsy, while epilepsy was only observed in 4/41 males. Among the 28 variants with available segregation reported, 19 were inherited from unaffected mothers and 9 were de novo. CONCLUSION: This study demonstrates that the BRWD3-related phenotypes are largely non-specific, leading to difficulty in clinical recognition of this disorder. A genotype-first approach, however, allows for the more efficient diagnosis of the BRWD3-related nonsyndromic ID. The refined clinical features presented here may provide additional diagnostic assistance for reverse phenotyping efforts.

Report on the p.Ser489X (p.Ser489*) CFTR mutation, a variant with severe associated phenotype and high prevalence in a Quebec French-Canadian cystic fibrosis patient population.

PURPOSE: This study reports on the phenotype of cystic fibrosis patients identified to be carriers of the p.Ser489X (p.Ser489*; c.1466C>A) cystic fibrosis transmembrane conductance regulator (CFTR) mutation, a variant rarely described in the cystic fibrosis literature, as well as on its allelic frequency in a French-Canadian cystic fibrosis patient cohort. METHODS: Reported phenotypes and allelic frequency of this variant were collected based on the data from a large French-Canadian cystic fibrosis patient cohort. RESULTS: Cystic fibrosis patients found to carry the p.Ser489X variant generally presented with classic gastrointestinal manifestations of this condition in infancy. The allelic frequency of this variant was calculated to be 0.7% for this population. CONCLUSION: The p.Ser489X CFTR variant is a severe disease-causing CFTR allele that is relatively frequent in the French-Canadian cystic fibrosis patient population, warranting its inclusion into CFTR molecular testing panel for this population.

MALDI-TOF mass array analysis of RASSF1A and SERPINB5 methylation patterns in human placenta and plasma.

Differences in DNA methylation patterns between placenta and blood cells of pregnant women have been suggested as potential biomarkers for noninvasive prenatal diagnostic strategies, including for common obstetrical complications, such as preeclampsia. New findings in epigenetic origins of fetal or placental disorders may improve our ability for optimal management of these conditions. Using a novel high-throughput mass spectrometry on matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass array, we compared the quantitative methylation changes of RASSF1 and SERPINB5 (also known as MASPIN) genes in placenta and plasma samples. We analyzed the methylation status of a total of 3569 CpG dinucleotides on these two genes in 83 different samples: 50 plasma samples (20 from pregnant women and 30 from nonpregnant women) and 33 placenta tissue samples (25 from normal pregnancies and eight from preeclamptic pregnancies). The aim of this study was to assess the utility of epigenetic changes as biomarkers for noninvasive prenatal diagnostic procedures. Using a two-way hierarchical cluster analysis, significantly different methylation levels of the RASSF1 gene were found between placenta (normal and preeclamptic) and plasma samples of pregnant women. Although the SERPINB5 gene was hypomethylated in placenta DNA more than in plasma DNA, it did not demonstrate significant differences between studied groups. The MALDI-TOF mass spectrometry analysis of placenta and plasma DNA methylation patterns may serve as a tool for the study of gender-independent biomarkers in noninvasive prenatal diagnosis.