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  1. Article ; Online: BRAT1 Mutation: The First Reported Case of Chinese Origin and Review of the Literature.

    Van Ommeren, Randy H / Gao, Andrew F / Blaser, Susan I / Chitayat, David A / Hazrati, Lili-Naz

    Journal of neuropathology and experimental neurology

    2018  Volume 77, Issue 12, Page(s) 1071–1078

    Abstract: Lethal neonatal rigidity and multifocal seizure syndrome (RMFSL) (OMIM#614498) is caused by homozygous or compound heterozygous mutation in the BRAT1 gene (OMIM#614506) on chromosome 7p22. We report a newborn female infant born to non-consanguineous ... ...

    Abstract Lethal neonatal rigidity and multifocal seizure syndrome (RMFSL) (OMIM#614498) is caused by homozygous or compound heterozygous mutation in the BRAT1 gene (OMIM#614506) on chromosome 7p22. We report a newborn female infant born to non-consanguineous Chinese parents who presented with hypertonia, dysmorphic features, progressive encephalopathy with refractory seizures, and worsening episodic apnea, leading to intubation and eventually death at 10 weeks of age. Whole exome sequencing revealed homozygous BRAT1 mutation, c.1395G>C (p.Thr465Thr), predicted to cause splice site disruption. Neuropathological assessment demonstrated microcephaly, severe neuronal loss, and background gliosis in the dorsal region of the putamen. Disruption of BRAT1 function in RMFSL has been proposed to cause dysfunction in the DNA damage response pathway and impair mitochondrial homeostasis. To our best knowledge this is the first reported case of Chinese origin. We review all published cases with BRAT1 mutation reported in the English literature and known BRAT1 functions which provide insight into the pathophysiology of the disease.
    MeSH term(s) Asian Continental Ancestry Group/genetics ; Brain/abnormalities ; Brain/diagnostic imaging ; Fatal Outcome ; Female ; Humans ; Infant ; Infant, Newborn ; Mutation/genetics ; Nuclear Proteins/genetics ; Seizures/diagnostic imaging ; Seizures/genetics
    Chemical Substances BRAT1 protein, human ; Nuclear Proteins
    Language English
    Publishing date 2018-10-22
    Publishing country England
    Document type Case Reports ; Journal Article ; Review
    ZDB-ID 3088-0
    ISSN 1554-6578 ; 0022-3069
    ISSN (online) 1554-6578
    ISSN 0022-3069
    DOI 10.1093/jnen/nly093
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus.

    Takai, Hiroyuki / Jenkinson, Emma / Kabir, Shaheen / Babul-Hirji, Riyana / Najm-Tehrani, Nasrin / Chitayat, David A / Crow, Yanick J / de Lange, Titia

    Genes & development

    2016  Volume 30, Issue 7, Page(s) 812–826

    Abstract: Coats plus (CP) can be caused by mutations in the CTC1 component of CST, which promotes polymerase α (polα)/primase-dependent fill-in throughout the genome and at telomeres. The cellular pathology relating to CP has not been established. We identified a ... ...

    Abstract Coats plus (CP) can be caused by mutations in the CTC1 component of CST, which promotes polymerase α (polα)/primase-dependent fill-in throughout the genome and at telomeres. The cellular pathology relating to CP has not been established. We identified a homozygous POT1 S322L substitution (POT1(CP)) in two siblings with CP. POT1(CP)induced a proliferative arrest that could be bypassed by telomerase. POT1(CP)was expressed at normal levels, bound TPP1 and telomeres, and blocked ATR signaling. POT1(CP)was defective in regulating telomerase, leading to telomere elongation rather than the telomere shortening observed in other telomeropathies. POT1(CP)was also defective in the maintenance of the telomeric C strand, causing extended 3' overhangs and stochastic telomere truncations that could be healed by telomerase. Consistent with shortening of the telomeric C strand, metaphase chromosomes showed loss of telomeres synthesized by leading strand DNA synthesis. We propose that CP is caused by a defect in POT1/CST-dependent telomere fill-in. We further propose that deficiency in the fill-in step generates truncated telomeres that halt proliferation in cells lacking telomerase, whereas, in tissues expressing telomerase (e.g., bone marrow), the truncations are healed. The proposed etiology can explain why CP presents with features distinct from those associated with telomerase defects (e.g., dyskeratosis congenita).
    MeSH term(s) Aminopeptidases/metabolism ; Ataxia/genetics ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Brain Neoplasms/genetics ; Calcinosis/genetics ; Cells, Cultured ; Central Nervous System Cysts/genetics ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism ; Female ; Humans ; Leukoencephalopathies/genetics ; Metaphase ; Muscle Spasticity/genetics ; Mutation/genetics ; Protein Binding ; Retinal Diseases/genetics ; Seizures/genetics ; Serine Proteases/metabolism ; Shelterin Complex ; Signal Transduction ; Telomere/genetics ; Telomere/metabolism ; Telomere/pathology ; Telomere Homeostasis/genetics ; Telomere Shortening/genetics ; Telomere-Binding Proteins/genetics
    Chemical Substances ACD protein, human ; Ctc1 protein, human ; POT1 protein, human ; Shelterin Complex ; Telomere-Binding Proteins ; ATR protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; Serine Proteases (EC 3.4.-) ; Aminopeptidases (EC 3.4.11.-) ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases (EC 3.4.14.-)
    Language English
    Publishing date 2016-03-24
    Publishing country United States
    Document type Case Reports ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 806684-x
    ISSN 1549-5477 ; 0890-9369
    ISSN (online) 1549-5477
    ISSN 0890-9369
    DOI 10.1101/gad.276873.115
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Semaphorin-Plexin Signaling: From Axonal Guidance to a New X-Linked Intellectual Disability Syndrome.

    Steele, Jacqueline L / Morrow, Michelle M / Sarnat, Harvey B / Alkhunaizi, Ebba / Brandt, Tracy / Chitayat, David A / DeFilippo, Colette P / Douglas, Ganka V / Dubbs, Holly A / Elloumi, Houda Zghal / Glassford, Megan R / Hannibal, Mark C / Héron, Bénédicte / Kim, Linda E / Marco, Elysa J / Mignot, Cyril / Monaghan, Kristin G / Myers, Kenneth A / Parikh, Sumit /
    Quinonez, Shane C / Rajabi, Farrah / Shankar, Suma P / Shinawi, Marwan S / van de Kamp, Jiddeke J P / Veerapandiyan, Aravindhan / Waldman, Amy T / Graf, William D

    Pediatric neurology

    2021  Volume 126, Page(s) 65–73

    Abstract: Background: Semaphorins and plexins are ligands and cell surface receptors that regulate multiple neurodevelopmental processes such as axonal growth and guidance. PLXNA3 is a plexin gene located on the X chromosome that encodes the most widely expressed ...

    Abstract Background: Semaphorins and plexins are ligands and cell surface receptors that regulate multiple neurodevelopmental processes such as axonal growth and guidance. PLXNA3 is a plexin gene located on the X chromosome that encodes the most widely expressed plexin receptor in fetal brain, plexin-A3. Plexin-A3 knockout mice demonstrate its role in semaphorin signaling in vivo. The clinical manifestations of semaphorin/plexin neurodevelopmental disorders have been less widely explored. This study describes the neurological and neurodevelopmental phenotypes of boys with maternally inherited hemizygous PLXNA3 variants.
    Methods: Data-sharing through GeneDx and GeneMatcher allowed identification of individuals with autism or intellectual disabilities (autism/ID) and hemizygous PLXNA3 variants in collaboration with their physicians and genetic counselors, who completed questionnaires about their patients. In silico analyses predicted pathogenicity for each PLXNA3 variant.
    Results: We assessed 14 boys (mean age, 10.7 [range 2 to 25] years) with maternally inherited hemizygous PLXNA3 variants and autism/ID ranging from mild to severe. Other findings included fine motor dyspraxia (92%), attention-deficit/hyperactivity traits, and aggressive behaviors (63%). Six patients (43%) had seizures. Thirteen boys (93%) with PLXNA3 variants showed novel or very low allele frequencies and probable damaging/disease-causing pathogenicity in one or more predictors. We found a genotype-phenotype correlation between PLXNA3 cytoplasmic domain variants (exons 22 to 32) and more severe neurodevelopmental disorder phenotypes (P < 0.05).
    Conclusions: We report 14 boys with maternally inherited, hemizygous PLXNA3 variants and a range of neurodevelopmental disorders suggesting a novel X-linked intellectual disability syndrome. Greater understanding of PLXNA3 variant pathogenicity in humans will require additional clinical, computational, and experimental validation.
    MeSH term(s) Adolescent ; Adult ; Autism Spectrum Disorder/genetics ; Autism Spectrum Disorder/physiopathology ; Cell Adhesion Molecules/physiology ; Child ; Child, Preschool ; Genetic Association Studies ; Humans ; Intellectual Disability/genetics ; Intellectual Disability/physiopathology ; Male ; Nerve Tissue Proteins/physiology ; Receptors, Cell Surface/genetics ; Semaphorins/physiology ; Signal Transduction/physiology ; Young Adult
    Chemical Substances Cell Adhesion Molecules ; Nerve Tissue Proteins ; PLXNA3 protein, human ; Receptors, Cell Surface ; Semaphorins ; plexin
    Language English
    Publishing date 2021-10-18
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639164-3
    ISSN 1873-5150 ; 0887-8994
    ISSN (online) 1873-5150
    ISSN 0887-8994
    DOI 10.1016/j.pediatrneurol.2021.10.008
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: 22q11.2 deletion syndrome: attitudes towards disclosing the risk of psychiatric illness.

    Martin, Nicole / Mikhaelian, Marina / Cytrynbaum, Cheryl / Shuman, Cheryl / Chitayat, David A / Weksberg, Rosanna / Bassett, Anne S

    Journal of genetic counseling

    2012  Volume 21, Issue 6, Page(s) 825–834

    Abstract: 22q11.2 Deletion Syndrome (22q11.2DS) is a common microdeletion syndrome with multisystem features. There is a strong association with psychiatric disorders. One in every four to five patients develop schizophrenia. Despite studies showing that early ... ...

    Abstract 22q11.2 Deletion Syndrome (22q11.2DS) is a common microdeletion syndrome with multisystem features. There is a strong association with psychiatric disorders. One in every four to five patients develop schizophrenia. Despite studies showing that early diagnosis and treatment are likely to lead to improved outcome, genetic counselors may be reluctant to discuss the risk of psychiatric illness. The aim of this research was to explore parental attitudes and genetic counselors' perspectives and practice regarding disclosure of the clinical manifestations of 22q11.2DS, particularly the risk of psychiatric illness. We delivered a questionnaire to genetic counselors via established list-serves, 54 of which were completed. We also conducted interviews with four parents of adults with 22q11.2DS and schizophrenia. The majority of counselors and parents felt that the increased risk to develop a psychiatric illness is important to disclose. However, in the initial counseling session when the diagnosis was made in infancy genetic counselors were significantly less likely to discuss the risk of psychiatric disorders compared to other later onset features such as hypothyroidism (41 % vs. 83 %, p = 0.001). When the diagnosis of 22q11.2DS was made in infancy, counselors' responses in regard to timing of disclosure about psychiatric illnesses were fairly evenly divided between infancy, childhood and adolescence. In contrast, for other major features of 22q11.2DS, disclosure would predominantly be in infancy. The respondents reported that the discussion of psychiatric issues with parents was challenging due to the stigma associated with mental illness. Some also noted limited knowledge about psychiatric illness and treatment. These results suggest that genetic counselors could benefit from further education regarding psychiatric illness in 22q11.2DS and best strategies for discussing this important subject with parents and patients.
    MeSH term(s) Attitude to Health ; Chromosome Deletion ; Chromosomes, Human, Pair 22 ; Genetic Counseling ; Humans ; Mental Disorders/psychology ; Risk Factors
    Language English
    Publishing date 2012-07-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1117799-8
    ISSN 1573-3599 ; 1059-7700
    ISSN (online) 1573-3599
    ISSN 1059-7700
    DOI 10.1007/s10897-012-9517-7
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  5. Article: Pregnancy outcome post renal transplantation.

    Sgro, Michael D / Barozzino, Tony / Mirghani, Hisham M / Sermer, Matthew / Moscato, Leah / Akoury, Hani / Koren, Gideon / Chitayat, David A

    Teratology

    2002  Volume 65, Issue 1, Page(s) 5–9

    Abstract: Background: The success in performing organ transplantations and prevention of rejection has resulted not only in a substantial increase in life expectancy, but also improvement in the patients' quality of life. Thus, women who underwent organ ... ...

    Abstract Background: The success in performing organ transplantations and prevention of rejection has resulted not only in a substantial increase in life expectancy, but also improvement in the patients' quality of life. Thus, women who underwent organ transplantation are now reaching puberty and the age of reproduction. This has presented new challenges regarding the teratogenicity and the long-term effect of immunosuppressive medications used by these patients. Previous studies have shown that pregnancies after renal transplantation are associated with an increased risk for both the mother and the fetus. There is, however, very little information available on neonatal and long-term pediatric follow-up of babies born to mothers who have undergone renal transplantation and have been exposed to immunosuppressive medications, compared to controls. We report the experience of our center, the largest in Canada, regarding the prenatal and long-term postnatal outcome of pregnancies after renal transplantation.
    Methods: This is a retrospective case series reporting the outcome of 44 consecutive pregnancies followed by the Toronto Renal Transplant Program. Follow-up data were gathered on the 32 live born children by either a return visit to the clinic or by telephone interview. Medical, as well as developmental information, was gathered on all children and the study group was compared to controls, matched for maternal age (+/-2 years) and smoking status, obtained through the Motherisk Program.
    Results: Of the 44 pregnancies followed by us, there were 32 live-born children delivered by 26 mothers and 12 stillborn/abortuses. Twenty-six pregnancies were treated with cyclosporine, azathioprine and prednisone, 13 with azathioprine and prednisone and five with cyclosporine and prednisone. The mean gestational age at delivery in the study group was 36.5 +/- 2.7 weeks compared to 40.2 +/- 1.6 weeks in the control group (P < 0.001). The mean birthweight in the study group was 2.54 +/- 0.67 kg, compared to 3.59 +/- 0.53 kg in the control group (P < 0.0001). In the study group there was one child with multiple anomalies and four stillbirths compared to zero in the control group. There were also six spontaneous abortions and two therapeutic abortions in the study group. On follow-up (from 3 months to 11 years of age) there was one child with insulin-dependent diabetes mellitus, two children with asthma and one child with recurrent otitis media. Developmental follow-up revealed one child with moderate to severe sensorineural hearing loss, one child with a learning disability and one child with pervasive developmental disorder. In none of these cases were there signs of perinatal asphyxia.
    Conclusion: There are significantly more stillbirths, preterm deliveries and increased incidence of low birth weight in the transplant group. Most pregnancies in the study group went well, however, and their offspring had normal postnatal growth and development. Further studies with long-term pediatric follow-up are needed to delineate their outcome and rule out possible long term effects of the immunosuppressive medication on their growth, development, reproduction and general health.
    MeSH term(s) Abortion, Spontaneous/etiology ; Adult ; Cyclosporine/adverse effects ; Female ; Fetal Growth Retardation/etiology ; Humans ; Immunosuppressive Agents/adverse effects ; Kidney Transplantation ; Obstetric Labor, Premature/etiology ; Pregnancy ; Pregnancy Complications ; Pregnancy Outcome ; Retrospective Studies ; Teratogens/pharmacology
    Chemical Substances Immunosuppressive Agents ; Teratogens ; Cyclosporine (83HN0GTJ6D)
    Language English
    Publishing date 2002-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 123029-3
    ISSN 1096-9926 ; 0040-3709
    ISSN (online) 1096-9926
    ISSN 0040-3709
    DOI 10.1002/tera.1092
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    Zs.A 749: Show issues Location:
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  6. Article ; Online: Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1.

    Crow, Yanick J / Chase, Diana S / Lowenstein Schmidt, Johanna / Szynkiewicz, Marcin / Forte, Gabriella M A / Gornall, Hannah L / Oojageer, Anthony / Anderson, Beverley / Pizzino, Amy / Helman, Guy / Abdel-Hamid, Mohamed S / Abdel-Salam, Ghada M / Ackroyd, Sam / Aeby, Alec / Agosta, Guillermo / Albin, Catherine / Allon-Shalev, Stavit / Arellano, Montse / Ariaudo, Giada /
    Aswani, Vijay / Babul-Hirji, Riyana / Baildam, Eileen M / Bahi-Buisson, Nadia / Bailey, Kathryn M / Barnerias, Christine / Barth, Magalie / Battini, Roberta / Beresford, Michael W / Bernard, Geneviève / Bianchi, Marika / Billette de Villemeur, Thierry / Blair, Edward M / Bloom, Miriam / Burlina, Alberto B / Carpanelli, Maria Luisa / Carvalho, Daniel R / Castro-Gago, Manuel / Cavallini, Anna / Cereda, Cristina / Chandler, Kate E / Chitayat, David A / Collins, Abigail E / Sierra Corcoles, Concepcion / Cordeiro, Nuno J V / Crichiutti, Giovanni / Dabydeen, Lyvia / Dale, Russell C / D'Arrigo, Stefano / De Goede, Christian G E L / De Laet, Corinne / De Waele, Liesbeth M H / Denzler, Ines / Desguerre, Isabelle / Devriendt, Koenraad / Di Rocco, Maja / Fahey, Michael C / Fazzi, Elisa / Ferrie, Colin D / Figueiredo, António / Gener, Blanca / Goizet, Cyril / Gowrinathan, Nirmala R / Gowrishankar, Kalpana / Hanrahan, Donncha / Isidor, Bertrand / Kara, Bülent / Khan, Nasaim / King, Mary D / Kirk, Edwin P / Kumar, Ram / Lagae, Lieven / Landrieu, Pierre / Lauffer, Heinz / Laugel, Vincent / La Piana, Roberta / Lim, Ming J / Lin, Jean-Pierre S-M / Linnankivi, Tarja / Mackay, Mark T / Marom, Daphna R / Marques Lourenço, Charles / McKee, Shane A / Moroni, Isabella / Morton, Jenny E V / Moutard, Marie-Laure / Murray, Kevin / Nabbout, Rima / Nampoothiri, Sheela / Nunez-Enamorado, Noemi / Oades, Patrick J / Olivieri, Ivana / Ostergaard, John R / Pérez-Dueñas, Belén / Prendiville, Julie S / Ramesh, Venkateswaran / Rasmussen, Magnhild / Régal, Luc / Ricci, Federica / Rio, Marlène / Rodriguez, Diana / Roubertie, Agathe / Salvatici, Elisabetta / Segers, Karin A / Sinha, Gyanranjan P / Soler, Doriette / Spiegel, Ronen / Stödberg, Tommy I / Straussberg, Rachel / Swoboda, Kathryn J / Suri, Mohnish / Tacke, Uta / Tan, Tiong Y / te Water Naude, Johann / Wee Teik, Keng / Thomas, Maya Mary / Till, Marianne / Tonduti, Davide / Valente, Enza Maria / Van Coster, Rudy Noel / van der Knaap, Marjo S / Vassallo, Grace / Vijzelaar, Raymon / Vogt, Julie / Wallace, Geoffrey B / Wassmer, Evangeline / Webb, Hannah J / Whitehouse, William P / Whitney, Robyn N / Zaki, Maha S / Zuberi, Sameer M / Livingston, John H / Rozenberg, Flore / Lebon, Pierre / Vanderver, Adeline / Orcesi, Simona / Rice, Gillian I

    American journal of medical genetics. Part A

    2015  Volume 167A, Issue 2, Page(s) 296–312

    Abstract: Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients ... ...

    Abstract Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.
    MeSH term(s) Adenosine Deaminase/genetics ; Autoimmune Diseases of the Nervous System/diagnosis ; Autoimmune Diseases of the Nervous System/genetics ; DEAD-box RNA Helicases/genetics ; Exodeoxyribonucleases/genetics ; Genetic Association Studies ; Genotype ; Humans ; Interferon-Induced Helicase, IFIH1 ; Interferons/blood ; Interferons/cerebrospinal fluid ; Monomeric GTP-Binding Proteins/genetics ; Mutation ; Nervous System Malformations/diagnosis ; Nervous System Malformations/genetics ; Phenotype ; Phosphoproteins/genetics ; Pterins/cerebrospinal fluid ; Ribonuclease H/genetics ; SAM Domain and HD Domain-Containing Protein 1
    Chemical Substances Phosphoproteins ; Pterins ; Interferons (9008-11-1) ; Exodeoxyribonucleases (EC 3.1.-) ; three prime repair exonuclease 1 (EC 3.1.16.-) ; ribonuclease HII (EC 3.1.26.-) ; Ribonuclease H (EC 3.1.26.4) ; SAM Domain and HD Domain-Containing Protein 1 (EC 3.1.5.-) ; SAMHD1 protein, human (EC 3.1.5.-) ; Adenosine Deaminase (EC 3.5.4.4) ; IFIH1 protein, human (EC 3.6.1.-) ; DEAD-box RNA Helicases (EC 3.6.4.13) ; Interferon-Induced Helicase, IFIH1 (EC 3.6.4.13) ; Monomeric GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2015-01-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2108614-X
    ISSN 1552-4833 ; 0148-7299 ; 1552-4825
    ISSN (online) 1552-4833
    ISSN 0148-7299 ; 1552-4825
    DOI 10.1002/ajmg.a.36887
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