Rare Copy Number Variants in Array-Based Comparative Genomic Hybridization in Early-Onset Skeletal Fragility

Early-onset osteoporosis is characterized by low bone mineral density (BMD) and fractures since childhood or young adulthood. Several monogenic forms have been identified but the contributing genes remain inadequately characterized. In search for novel variants and novel candidate loci, we screened a cohort of 70 young subjects with mild to severe skeletal fragility for rare copy-number variants (CNVs). Our study cohort included 15 subjects with primary osteoporosis before age 30 years and 55 subjects with a pathological fracture history and low or normal BMD before age 16 years. A custom-made high-resolution comparative genomic hybridization array with enriched probe density in >1,150 genes important for bone metabolism and ciliary function was used to search for CNVs. We identified altogether 14 rare CNVs. Seven intronic aberrations were classified as likely benign. Five CNVs of unknown clinical significance affected coding regions of genes not previously associated with skeletal fragility (ETV1-DGKB, AGBL2, ATM, RPS6KL1-PGF, and SCN4A). Finally, two CNVs were pathogenic and likely pathogenic, respectively: a 4 kb deletion involving exons 1-4 of COL1A2 (NM_000089.3) and a 12.5 kb duplication of exon 3 in PLS3 (NM_005032.6). Although both genes have been linked to monogenic forms of osteoporosis, COL1A2 deletions are rare and PLS3 duplications have not been described previously. Both CNVs were identified in subjects with significant osteoporosis and segregated with osteoporosis within the families. Our study expands the number of pathogenic CNVs in monogenic skeletal fragility and shows the validity of targeted CNV screening to potentially pinpoint novel candidate loci in early-onset osteoporosis.Peer reviewe

Rare variants in dynein heavy chain genes in two individuals with situs inversus and developmental dyslexia : a case report

Background Developmental dyslexia (DD) is a neurodevelopmental learning disorder with high heritability. A number of candidate susceptibility genes have been identified, some of which are linked to the function of the cilium, an organelle regulating left-right asymmetry development in the embryo. Furthermore, it has been suggested that disrupted left-right asymmetry of the brain may play a role in neurodevelopmental disorders such as DD. However, it is unknown whether there is a common genetic cause to DD and laterality defects or ciliopathies. Case presentation Here, we studied two individuals with co-occurring situs inversus (SI) and DD using whole genome sequencing to identify genetic variants of importance for DD and SI. Individual 1 had primary ciliary dyskinesia (PCD), a rare, autosomal recessive disorder with oto-sino-pulmonary phenotype and SI. We identified two rare nonsynonymous variants in the dynein axonemal heavy chain 5 gene (DNAH5): a previously reported variant c.7502G > C; p.(R2501P), and a novel variant c.12043 T > G; p.(Y4015D). Both variants are predicted to be damaging. Ultrastructural analysis of the cilia revealed a lack of outer dynein arms and normal inner dynein arms. MRI of the brain revealed no significant abnormalities. Individual 2 had non-syndromic SI and DD. In individual 2, one rare variant (c.9110A > G;p.(H3037R)) in the dynein axonemal heavy chain 11 gene (DNAH11), coding for another component of the outer dynein arm, was identified. Conclusions We identified the likely genetic cause of SI and PCD in one individual, and a possibly significant heterozygosity in the other, both involving dynein genes. Given the present evidence, it is unclear if the identified variants also predispose to DD and further studies into the association between laterality, ciliopathies and DD are needed.Peer reviewe

Rare Copy Number Variants in Array-Based Comparative Genomic Hybridization in Early-Onset Skeletal Fragility

Early-onset osteoporosis is characterized by low bone mineral density (BMD) and fractures since childhood or young adulthood. Several monogenic forms have been identified but the contributing genes remain inadequately characterized. In search for novel variants and novel candidate loci, we screened a cohort of 70 young subjects with mild to severe skeletal fragility for rare copy-number variants (CNVs). Our study cohort included 15 subjects with primary osteoporosis before age 30 years and 55 subjects with a pathological fracture history and low or normal BMD before age 16 years. A custom-made high-resolution comparative genomic hybridization array with enriched probe density in >1,150 genes important for bone metabolism and ciliary function was used to search for CNVs. We identified altogether 14 rare CNVs. Seven intronic aberrations were classified as likely benign. Five CNVs of unknown clinical significance affected coding regions of genes not previously associated with skeletal fragility (ETV1-DGKB, AGBL2, ATM, RPS6KL1-PGF, and SCN4A). Finally, two CNVs were pathogenic and likely pathogenic, respectively: a 4 kb deletion involving exons 1–4 of COL1A2 (NM_000089.3) and a 12.5 kb duplication of exon 3 in PLS3 (NM_005032.6). Although both genes have been linked to monogenic forms of osteoporosis, COL1A2 deletions are rare and PLS3 duplications have not been described previously. Both CNVs were identified in subjects with significant osteoporosis and segregated with osteoporosis within the families. Our study expands the number of pathogenic CNVs in monogenic skeletal fragility and shows the validity of targeted CNV screening to potentially pinpoint novel candidate loci in early-onset osteoporosis

Prospectus, April 11, 1984

FROM COBRA TO WHAT? COLOR AND NICKNAME CHANGE CONSIDERED; News Digest; Editorial; We want your contributions; Ride for friends; Crime rate rises in Champaign; Graduating needs; PC Happenings: \u27Saboteurs of job success\u27 is program topic, Lifelong learners discuss writing, Parkland choral group performs, Vietnam veterans to meet, Health Fair to be held, Election changes discussed, Petitions available for Stu-Go; FSM dinner enjoyed by all; Easter egg hunt; Ham is what\u27s cookin\u27 for Easter this year; Alcohol a problem at county jail; Changes for Parkland\u27s Pharmacy Technology program; Book Review: Knock Wood by Candice Bergen; Did You Know...; Swanson awarded scholarship; Creative Corner...Especially for you!!: The Painting, Rejoice the Poet, The Wind of the Phoenix, Bodies, The search for truth and beauty is hard and painful..., A Special Lady, Home is where the heart is..., I have tried to be just your friend..., Rites of passage; Parkland\u27s third Open House attracts over 4,000 visitors: Friendly, inviting atmosphere impresses visitors; Classifieds; Question: What impressed you about Parkland?; Krannert schedule for \u2784-\u2785; Campus Paperback Bestsellers; New & Recommended; Greystoke explores duality of man; Slade tries for \u27comeback\u27; WILL repeats Hitchhiker\u27s; PC track needs participation; Karate demo at Parkland; Parkland Prospectus survey; Sports Digest; Braves to edge out Dodgershttps://spark.parkland.edu/prospectus_1984/1025/thumbnail.jp

Prospectus, May 10, 1984

COPIES ARE AVAILABLE FOR \u27IMAGES\u27; StuGo election results; Staerkel talks about scholarships; News Digest; Letter to the editor: Separate Women\u27s Program vital for the women who have invested so much in you; PC Happenings; Hard work recognized by Dean; Letter from the editor: Human element was always there; Editor says goodbye; \u27Intellectual Freedom Begins Here\u27; Student art exhibit displayed variety; Everyone enjoys four-day week during summer session; Law clerk tells how the judicial system really works; Eddie Albert plots ready to grow; Cribbet to speak at Commencement; Students and organizations honored at awards banquet; Creative Corner...Especially for you!!; Freedom; Cathy; This is Dedicated to Amy; Too Late; Almost There; Unwritten; The Life and Death of a Friendship; Parkland\u27s year the was--83/84--awards, scholarships, sports and fun; Classifieds; Did you know...; International songwriters competition; College Bowl National; Pretenders release latest and Rock Goddess their first; \u27Sixteen Candles\u27 burns out; Films show promise this summer; Winter wind blows hot; \u27Indiana Jones\u27 and \u27Spock\u27 lead the way at movies; Instructor receives award; Spring Out; StuGo purchases new van; Sports Digest; N.A.I.A. kills plan; 1984 Parkland outdoor track bests; L.A. students try to trust the Olympics; Baseball team ends season; 1984 Graduates and Candidates for Graduationhttps://spark.parkland.edu/prospectus_1984/1021/thumbnail.jp

Prospectus, April 18, 1984

CHORAL UNION DEMANDING AND REWARDING; News Digest; Is your child part of the identi-child program?; Budding playwrights get chance to have work produced; PC Happenings: Parkland wins Automotive Contest, German Club annual Springfest, EMT workshop offered, Petitions available for Stu-Go, Stu-Go lacks quorum; Here Comes the Easter Bunny (or the Easter Hare?); Faces We Make; Former Prospectus entertainment writer: Alender services held; Strange things at the library; Only Food Service Management course in area: Sutton leads Food Service Management program; Criminal justice program well rounded; Running may increase protein need; Easter means Easter egg time; Second Wind hosts race; Did You Know...; Classifieds; Creative Corner...Especially for you!!: Recollections, She\u27s More than a Nurse, You are a corn-fed steak..., Memories..., A fire burns, AKTING??????????????..., Sometimes in their heed to tact..., Clouds, Disturb Not the Dead, Follow the Wind, I don\u27t know why I bother..., Innoncent Eyes, Please tell me what it is you want..., Running scared from yourself and tripped, babe..., Time Bomb, Don\u27t go away--Linger on..., Class, Raggedy Ann lay in the back of an old station wagon..., Too Late, To God; Ice Capades comes to town: Skaters say it\u27s hard work but well worth it; few surprises during Hollywood\u27s biggest night; \u27Queen\u27 film at Assembly Hall; Director shines in film; \u27Go-Go\u27s\u27 are back on track; \u27Weird Al\u27 hits big time; Fan Club to host film; Parkland College 1984 baseball roster; Cobra men lose two; 1984 Parkland Outdoor Track Bests; Sports Digest; Women lose twin bill; Prospectus survey resultshttps://spark.parkland.edu/prospectus_1984/1024/thumbnail.jp

Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP

Background In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking. Methods We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires. Results We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected. Conclusions This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.This work was supported by grants from the European Research Area Networks Network of European Funding for Neuroscience Research through the Research Foundation–Flanders and the Chief Scientist Office–Ministry of Health (to RFK, GV, IG). This research was supported, in part, by grants from the Simons Foundation Autism Research Initiative (Grant No. SFARI 303241 to EEE) and National Institutes of Health (Grant No. R01MH101221 to EEE). This work was also supported by the Italian Ministry of Health and ‘5 per mille’ funding (to CR). For many individuals, sequencing was provided by research initiatives like the Care4Rare Research Consortium in Canada or the Deciphering Developmental Disorders (DDD) study in the UK. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (Grant No. HICF-1009–003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (Grant No. WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South Research Ethics Committee, and GEN/284/12 granted by the Republic of Ireland Research Ethics Committee). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network