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Clinical and Genetic Characteristics and Prenatal Diagnosis of Patients Lin et al. Orphanet J Rare Dis (2020) 15:317 https://doi.org/10.1186/s13023-020-01599-y RESEARCH Open Access Clinical and genetic characteristics and prenatal diagnosis of patients presented GDD/ID with rare monogenic causes Liling Lin1, Ying Zhang1, Hong Pan1, Jingmin Wang2, Yu Qi1 and Yinan Ma1* Abstract Background: Global developmental delay/intellectual disability (GDD/ID), used to be named as mental retardation (MR), is one of the most common phenotypes in neurogenetic diseases. In this study, we described the diagnostic courses, clinical and genetic characteristics and prenatal diagnosis of a cohort with patients presented GDD/ID with monogenic causes, from the perspective of a tertiary genetic counseling and prenatal diagnostic center. Method: We retrospectively analyzed the diagnostic courses, clinical characteristics, and genetic spectrum of patients presented GDD/ID with rare monogenic causes. We also conducted a follow-up study on prenatal diagnosis in these families. Pathogenicity of variants was interpreted by molecular geneticists and clinicians according to the guidelines of the American College of Medical Genetics and Genomics (ACMG). Results: Among 81 patients with GDD/ID caused by rare monogenic variants it often took 0.5–4.5 years and 2–8 referrals to obtain genetic diagnoses. Devlopmental delay typically occurred before 3 years of age, and patients usu- ally presented severe to profound GDD/ID. The most common co-existing conditions were epilepsy (58%), micro- cephaly (21%) and facial anomalies (17%). In total, 111 pathogenic variants were found in 62 diferent genes among the 81 pedigrees, and 56 variants were novel. The most common inheritance patterns in this outbred Chinese popula- tion were autosomal dominant (AD; 47%), following autosomal recessive (AR; 37%), and X-linked (XL; 16%). SCN2A, SHANK3 and STXBP1 were important causal genes. Hot-spot variants were rarely found. By the follow-up, 33 afected families, including 15, 13 and 5 families inherited in AR, AD and XL modes respectively, had undergone prenatal diag- nosis. And the recurrence rates are 26.7%, 15.4% and 20% for families inherited in AR, AD, and XL patterns. Conclusion: Patients presented with GDD/ID caused by rare single gene variants are characterized by early onset, relatively severe symptoms and great clinical variability and genetic heterogeneity. Timely referrals to genetic coun- seling and prenatal diagnostic laboratories are important for afected families planning to have additional children. Keywords: Global developmental delay and intellectual disability (GDD/ID), Monogenic disease, Prenatal diagnosis, Next-generation sequencing Introduction Global developmental delay/intellectual disability (GDD/ID), used to be named as mental retardation (MR) is one of the most common phenotypes in neu- rogenetic diseases. Global developmental delay (GDD), *Correspondence: [email protected] is characterized by a delay in achieving developmental 1 Department of Central Laboratory, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing 100034, China milestones in at least two of the following domains: Full list of author information is available at the end of the article motor skills, speech and language, cognitive skills, and © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Lin et al. Orphanet J Rare Dis (2020) 15:317 Page 2 of 15 social and emotional skills [1]. After growing up, many Material and methods patients with GDD would demonstrate intellectual dis- Study design and participants ability (ID), which is characterized by an intelligence From June 2015 to June 2019, we recruited 81 consecu- quotient below 70 and limitations on adaptability [1, 2]. tive subjects under 18 years old who presented GDD/ Te prevalence of GDD/ID in the world population is ID with rare monogenic causes. Te clinical diagnosis of estimated to be 1–3% [3], and the average lifetime costs GDD/ID was made according to the Diagnostic and Sta- (direct and indirect) to support an individual with ID tistical Manual of Mental Disorders, 5th edition (DSM- have reached $1 million [4, 5]. V) [2]. GDD was defned by delays in the achievement Various environmental and genetic factors can of motor or mental milestones in the following domains: result in GDD/ID [6]. Genetic reasons, including ane- gross and fne motor skills, speech and language, adapta- uploidy, copy number variants and single gene variants, bility and social skills. A developmental scale for children account for 30–50% of cases [7], and Down syndrome, aged 0–5 years [15] was used to assess the Developmen- MECP2-related Rett syndrome and fragile X syndrome tal Quotient (DQ) for children who were under 5 years are the most common forms of genetic GDD/ID [6]. old or failed to fnish the intelligence test. Patients with Te modes of inheritance of genes related to GDD/ID a DQ of less than 75 in at least two of fve developmen- include autosomal recessive (AR), autosomal dominant tal domains were diagnosed with GDD. For patients (AD), X-linked (XL) and mitochondrial [8]. On the over 5 years old, we used the Wechsler Intelligence Scale basis of inherited patterns, some scholars divided those for Children (WISC) to quantify IQ. Tose who had IQ genes into ARID (autosomal recessive intellectual disa- scores lower than 70 and adaptability difculties were bility), ADID (autosomal dominant intellectual disabil- diagnosed with ID. Te tests were performed by special- ity) and XLID (X-linked intellectual disability) [9–11]. ists in child development. With the improvement of next-generation sequenc- For etiological diagnosis, according to the guideline ing (NGS) [12], monogenic genetic causes are being proposed by American Psychiatric Association (APA) found more frequently in previously unexplained or idi- in 2014 [1] and Chinese Medical Association(CMA) in opathic cases. To date, nearly 1334 causative genes and 2018 [16], all patients underwent systematically examina- 1159 candidate genes have been identifed as related to tions, comprising medical history, physical examination, GDD/ID [13], and the number continues to grow. metabolic tests and neuroimaging study (brain MRI/CT) With increasing number of patients have obtained to exclude non genetic causes and underwent necessary the genetic diagnoses by NGS, it poses great challenges genetic tests, such as G-band karyotyping, FMR1 CGG on subsequential genetic counseling for family repro- repeat testing [17], and CMA testing [18], to exclude duction plan because of our limited knowledge on most other genetic reasons. Sanger sequencing or Trio-NGS rare monogenic diseases. As efective and specifc treat- [19, 20], including targeted exome sequencing (panel) or ments for most monogenic diseases are still in develop- whole exome sequencing (WES) was performed depend- ment, and prenatal molecular diagnosis is an important ing on clinical judgment. Te details of the detection method to prevent recurrence. Previous studies mainly methods are reported elsewhere. focused on comparing the diagnostic yields of diferent Te fnal clinical and genetic diagnoses were deter- NGS methods [14] on unidentifed GDD/ID or expand- mined by a group of pediatric neurologists, clinical ing the phenotype and genotype spectrum of a genetic geneticists and molecular geneticists. Te Ethics Com- disorder or specifc gene. However, the general charac- mittee of Peking University First Hospital approved the teristics of patients presented GDD/ID with rare mono- study (2020-333). Informed consent was obtained from genic causes have not been well studied. Besides, few all participants. studies concerned the genetic counseling and prenatal diagnosis. Data collection In this article, we collected a cohort of patients with Demographic data, medical history, laboratory and GDD/ID caused by rare single gene variants. It is the genetic fndings were collected. Te severity of GDD/ID frst time, to the best of our knowledge, to observed was classifed into four groups: mild, moderate, severe these patients from the perspective of a genetic coun- and profound, defned by DQ (IQ) scores of 55–75 (50– seling and prenatal diagnostic center. Te frst aim of 69), 40–54 (35–49), 25–39 (20–34), and below 25 (20), the study was to describe the diagnostic courses and respectively. Te age at disease onset was calculated as clinical and genetic spectrum of these patients. Te the interval from the date of birth to the date when the second aim was to report prenatal molecular diagnostic frst symptom was noticed. Te age at diagnosis was cal- results of afected families, intending to raise awareness culated as the interval from the date of birth to the date on this area. when genetic diagnosis was confrmed. Te interval Lin et al. Orphanet J Rare Dis (2020) 15:317 Page 3 of 15 between symptom onset and diagnosis was obtained as Ensembl (VEP) [33] and PubMed to determine whether the age at diagnosis minus the age at disease onset. Te the variant had been reported previously.
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