Clinical experience with non-invasive prenatal screening for single-gene disorders.

OBJECTIVE: To assess the performance of a non-invasive prenatal screening test (NIPT) for a panel of dominant single-gene disorders (SGD) with a combined population incidence of 1 in 600. METHODS: Cell-free fetal DNA isolated from maternal plasma samples accessioned from 14 April 2017 to 27 November 2019 was analyzed by next-generation sequencing, targeting 30 genes, to look for pathogenic or likely pathogenic variants implicated in 25 dominant conditions. The conditions included Noonan spectrum disorders, skeletal disorders, craniosynostosis syndromes, Cornelia de Lange syndrome, Alagille syndrome, tuberous sclerosis, epileptic encephalopathy, SYNGAP1-related intellectual disability, CHARGE syndrome, Sotos syndrome and Rett syndrome. NIPT-SGD was made available as a clinical service to women with a singleton pregnancy at ≥ 9 weeks' gestation, with testing on maternal and paternal genomic DNA to assist in interpretation. A minimum of 4.5% fetal fraction was required for test interpretation. Variants identified in the mother were deemed inconclusive with respect to fetal carrier status. Confirmatory prenatal or postnatal diagnostic testing was recommended for all screen-positive patients and follow-up information was requested. The screen-positive rates with respect to the clinical indication for testing were evaluated. RESULTS: A NIPT-SGD result was available for 2208 women, of which 125 (5.7%) were positive. Elevated test-positive rates were observed for referrals with a family history of a disorder on the panel (20/132 (15.2%)) or a primary indication of fetal long-bone abnormality (60/178 (33.7%)), fetal craniofacial abnormality (6/21 (28.6%)), fetal lymphatic abnormality (20/150 (13.3%)) or major fetal cardiac defect (4/31 (12.9%)). For paternal age ≥ 40 years as a sole risk factor, the test-positive rate was 2/912 (0.2%). Of the 125 positive cases, follow-up information was available for 67 (53.6%), with none classified as false-positive. No false-negative cases were identified. CONCLUSIONS: NIPT can assist in the early detection of a set of SGD, particularly when either abnormal ultrasound findings or a family history is present. Additional clinical studies are needed to evaluate the optimal design of the gene panel, define target populations and assess patient acceptability. NIPT-SGD offers a safe and early prenatal screening option. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

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.

Acute Intermittent Porphyria: A Diagnostic Conundrum.

This case report presents the case of a 20-year-old female patient who sought emergency medical attention for severe abdominal pain, nausea and vomiting, tachycardia, hypertension, and discolored urine. Initial diagnostic evaluations yielded no significant abnormalities; however, subsequent analysis revealed elevated urinary porphobilinogen, corroborating a diagnosis of acute intermittent porphyria (AIP). The patient's medical history included recurrent urinary tract infections and a prior episode of syndrome of inappropriate antidiuretic hormone secretion (SIADH), in conjunction with psychiatric comorbidities of anxiety and depression. Management encompassed a multifaceted approach involving supportive therapies, such as hydration and analgesia, alongside the imperative to abstain from using contraindicated pharmacological agents. Following referral to the National Acute Porphyria Service (NAPS), the patient received intravenous Haem arginate, resulting in clinical improvement and subsequent discharge. Nonetheless, she later necessitated further hospitalization due to the recurrence of similar symptoms. This case highlights the exigency of recognizing AIP in young women presenting with nonspecific symptoms, necessitating a high index of clinical suspicion. Furthermore, it accentuates the critical importance of early specialist intervention to avert severe sequelae associated with acute episodes. The integration of targeted educational initiatives within Acute Medicine departments is paramount for fostering awareness and facilitating prompt diagnosis and management of this rare yet significant disorder.

Not All Chubby Cheeks Are Cute: A Case of Cherubism.

The growth of the jaw occurs painlessly in cherubism, a rare genetic disorder where normal bone is replaced by fibrous tissue and undeveloped bone. Usually running in families, this non-cancerous genetic condition naturally reaches a limit and stops growing. The main characteristic is the aberrant growth of osseous and fibrous tissue in the maxilla and mandible, which is frequently seen in children. Cherubism is inherited autosomal dominantly, though reports have included individuals without a family history. The disorder has specific radiographic and histological features that drastically affect facial appearance. This article provides a thorough case study of a male 16-year-old with cherubism, emphasizing management techniques and clinical and radiological results. Radiological imaging is essential for diagnosis and management because it can identify the distinctive features of cherubism and the treatment implications associated with it.

HDR syndrome, detected in the neonatal period by newborn hearing screening.

Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is an autosomal dominant disorder. Because HDR syndrome is caused by haploinsufficiency in GATA3, it exhibits variation in the onset and progression of hearing loss. In previous reports, the automated auditory brainstem response (AABR) was considered insufficient to detect sensorineural hearing loss caused by HDR syndrome. We report a case of HDR syndrome whose congenital hearing loss was detected by newborn hearing screening (NHS) using AABR. In this case, HDR syndrome was suspected due to hearing loss, hypocalcemia, and her family history. Genetic testing confirmed the diagnosis of HDR syndrome at 5 months of age. Because the phenotype of hearing loss due to HDR syndrome is variable and includes progressive hearing loss, these cases may not be detected by the HNS. However, most of the previous reports were published before the NHS became common and given the frequency of hearing loss complications in HDR syndrome. We consider that there is a reasonable number of HDR syndrome cases with abnormalities on the NHS. We believe that the NHS may also be useful for early detection of hearing loss due to HDR syndrome.

To Test or Not to Test: A Case Report on Hereditary Hemorrhagic Telangiectasia.

A 50-year-old female patient presenting with joint pains, Raynaud's phenomenon, epistaxis, and telangiectasias was posed with a diagnostic conundrum, i.e., whether to accept the diagnosis of mixed connective tissue disease (MCTD), for which she fulfilled all the criteria, or test for another probable disease, namely hereditary hemorrhagic telangiectasia (HHT), even though only some clinical features were present and all diagnostic criteria were not satisfied. Taking the patient's onset of epistaxis as an important clue, the patient was counseled for genetic testing for HHT, which was positive. Treatment for both MCTD and HHT is underway, and appropriate surveillance is planned for the patient.

Autosomal Dominant Pseudohypoaldosteronism Type 1 in a Newborn With Failure to Thrive.

Pseudohypoaldosteronism type 1 is a rare genetic disorder characterized by salt wasting and resistance to mineralocorticoids due to mutations in the NR3C2 gene which codes for the aldosterone receptor proteins in the kidneys. This case study involves an infant who presented with poor growth and significant hyponatremia. There was improvement in growth and correction of hyponatremia with sodium supplementation, later found to carry a new genetic variant causing autosomal dominant pseudohypoaldosteronism type 1. A 14-day-old newborn presented with failure to thrive, severe hyponatremia, mild hyperkalemia, and metabolic acidosis. The electrolyte abnormalities were corrected with intravenous fluid and sodium supplementation. Continued oral sodium supplementation led to improved weight gain. Clinical suspicion and subsequent diagnostic testing led to a diagnosis of the autosomal dominant renal form of pseudohypoaldosteronism type 1. Genetic testing revealed a novel mutation on the NR3C2 gene, c.556_557del (p.Met186Valfs*3). The baby was discharged home on supplemental sodium and high-calorie formula for catch-up growth. Outpatient follow-up is ongoing.

Family with Peutz-Jeghers syndrome in Indonesia.

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder characterised by mucocutaneous pigmentation, gastrointestinal polyps and an increased risk of gastrointestinal and other cancers. We report an Indonesian woman, aged 28, with black spots on her lips who had multiple polyps extending from the stomach to the rectum. Her father and a son also had mucocutaneous lesions but they did not undergo gastrointestinal investigations. All three had mutations in the serine/threonine kinase 11 gene (STK11).

Hepatocyte nuclear factor 1B mutation in a Chinese family with renal cysts and diabetes syndrome: A case report.

BACKGROUND: Renal cysts and diabetes (RCAD) syndrome is an autosomal dominant diabetic renal disease. Precise molecular diagnosis of RCAD syndrome has proven valuable for understanding its mechanism and personalized therapy. CASE SUMMARY: A RCAD patient and her family were studied to investigate potential responsible genes by the whole exome sequencing (WES). Candidate pathogenic variants were validated by Sanger sequencing. The clinical characteristics of RCAD patient were collected from medical records. Unlike those typical RCAD patients, we observed renal manifestation and prediabetes phenotype, but not reproductive organ phenotype and hypomagnesaemia. A novel 7-bp deletion mutation in exon 4 of the hepatocyte nuclear factor 1B, NM_000458: c.882_888del (p.V294fs), was identified by WES and confirmed by Sanger sequencing. CONCLUSION: This novel mutation identified in a Chinese family with RCAD syndrome might be the molecular pathogenic basis of this disorder.

Can sudden cardiac death in the young be predicted and prevented? Lessons from autopsy for the emergency physician. / ¿Se puede predecir y prevenir la muerte súbita cardiaca en sujetos jóvenes? Algunas indicaciones para el urgenciólogo.

OBJECTIVES: Sudden unexpected death in the young, though rare, is devastating for both the family and the community. Although only 1.3 to 8.5 cases of sudden cardiac death (SCD) occur per 100 000 young people, autopsy is often inconclusive. Many causes of SCD are related to autosomal dominant inherited risk, however; therefore, answers are important for survivors. Causes of autopsy-positive SCD in young patients include hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia. Autopsy-negative SCD has been related to inherited arrhythmogenic causes such as long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, Wolff- Parkinson-White syndrome, and idiopathic ventricular fibrillation. The important question for the emergency physician is how SCD can be predicted and prevented in the young so that there is no need for an autopsy.

ES: La muerte súbita e inesperada en jóvenes es un evento raro pero devastador. Aunque su incidencia es baja, se registran de 1,3 a 8,5 casos de muerte súbita cardiaca (MSC) por cada 100.000 jóvenes y se asocia frecuentemente con una autopsia negativa. Muchas de las causas de la MSC con autopsia negativa se heredan de forma autosómica dominante. Algunas causas de MSC con autopsia positiva en pacientes jóvenes incluyen la miocardiopatía hipertrófica (MCH) y la displasia arritmogénica de ventriculo derecho. Las causas de autopsia negativa incluyen causas arritmogénicas heredadas, como el síndrome de QT largo, el síndrome de Brugada, la taquicardia ventricular polimórfica catecolaminérgica, el syndrome de Wolff-Parkinson-White (WPW) y la fibrilación ventricular idiopática. La pregunta importante para los profesionales de urgencias es: ¿cómo podemos predecir y prevenir la MSC en los jóvenes antes de la autopsia?

Whole-exome sequencing identifies a novel IHH insertion in an Ontario family with brachydactyly type A1.

Isolated brachydactyly is an umbrella term describing disproportionally shortened fingers and toes, often following an autosomal dominant mode of inheritance. Various forms of brachydactyly have been characterized and several causative genes have been found, but many types remain genetically undefined. We describe an Ontario family with mild brachydactyly in which whole-exome sequencing identified a novel variant for brachydactyly type A1 (exon 1, c.285_287dupGAA, p.Glu95_Asn96insLys) in the Indian hedgehog (IHH) gene. This rare variant co-segregated with affected status in the pedigree and was associated with (1) shortened middle phalange length by 21.1% (p < 0.001); (2) shortened palm length by 13.8% (p < 0.01); (3) reduced digit-palm ratio by 6.8% (p < 0.03); and (4) reduced stature by 9.5% (p < 0.001). We report the first IHH in-frame insertion causing brachydactyly type A1.

Spinal cord ependymoma associated with neurofibromatosis 1 : case report and review of the literature.

Patients with neurofibromatosis 1 (NF1) are predisposed to develop central nervous system tumors, due to the loss of neurofibromin, an inactivator of proto-oncogene Ras. However, to our knowledge, only three cases of ependymomas with NF1 have been reported in the literature. The authors present a case of NF1 patient with a spinal cord ependymoma. She was referred for about half a year history of increasing numbness that progressed from her fingers to her entire body above the bellybutton. Magnetic resonance imaging revealed a relative-demarcated, heterogeneously enhanced mass lesion accompanied by perifocal edema in C5-7 level, a left-sided T11 spinous process heterogeneously enhanced mass in soft tissue, intervertebral disk hernia in L2-5 level, and widespread punctum enhancing lesion in her scalp and in T11-L5 level. The patient underwent C5-7 laminectomies and total excision of the tumor under operative microscope, and intraoperative ultrasonography and physiological monitoring were used during the surgery. Histopathologically, her tumor was found to be a ependymoma without malignant features (grade II in the World Health Organization classification). Therefore, no adjuvant therapy was applied. Following the operation, the patient showed an uneventful clinical recovery with no evidence of tumor recurrence after one year of follow-up.

Popliteal pterygium syndrome: a rare entity.

The popliteal pterygium syndrome is a congenital malformation that includes orofacial, musculoskeletal and genitourinary anomalies. It is a rare autosomal dominant disorder. We report one family with popliteal pterygium syndrome affecting father and his two daughters, who underwent surgical corrections for multiple congenital malformations.