Inspired by a colleague's patient
Schirwani S, Albaba S, Carere DA, Guillen Sacoto MJ, Milan Zamora F, Si Y, Rabin R, Pappas J, Renaud DL, Hauser N, Reid E, Blanchet P, Foulds N, Dixit A, Fisher R, Armstrong R, Isidor B, Cogne B, Schrier Vergano S, Demirdas S, Dykzeul N, Cohen JS, Grand K, Morel D, Slavotinek A, Albassam HF, Naik S, Dean J, Ragge N, Cinzia C, Tedesco MG, Harrison RE, Bouman A, Palen E, Challman TD, Willemsen MH, Vogt J, Cunniff C, Bergstrom K, Walia JS, Bruel AL, Kini U, Alkuraya FS, Slegesky V, Meeks N, Girotto P, Johnson D; DDD Study, Newbury-Ecob R, Ockeloen CW, Prontera P, Lynch SA, Li D, Graham JM Jr, Balasubramanian M. Expanding the phenotype of ASXL3-related syndrome: A description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3. Am J Med Genet A. 2021 Nov;185(11):3446-3458. doi: 10.1002/ajmg.a.62465. Epub 2021 Aug 26. PMID: 34436830.
The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.
Ikekwere JC, Osuagwu FC, LePlatte D, Ghaziuddin M. Comorbid Psychiatric Aspects of Bainbridge-Ropers Syndrome. Prim Care Companion CNS Disord. 2021 Jun 3;23(3):20m02783. doi: 10.4088/PCC.20m02783. PMID: 34086428.
Objective: Bainbridge-Ropers syndrome (BRPS) is a neurodevelopmental genetic disorder associated with mutations in the additional sex combs-like ASXL3 gene on chromosome 18q12.1. The objective of this study is to describe the comorbid psychiatric aspects of BRPS.
Methods: A retrospective review was conducted of the electronic medical records of patients diagnosed with BRPS from 2013 to 2020 at an academic medical center. Results were deidentified and presented as frequencies and percentages.
Results: Seven cases (5 White males and 2 White females) of BRPS were identified. The mean age at the time of referral was 12 years, while the mean age at diagnosis of BRPS was 7 years. Comorbid psychiatric symptoms and diagnoses associated with BRPS included global developmental delay: 6 (86%), sleep impairment: 5 (71%), autism spectrum disorder: 3 (43%), speech impairment: 2 (29%), disruptive behavior: 4 (57%), attention-deficit/hyperactivity disorder: 3 (43%), self-injurious behavior: 3 (43%), aggression: 4 (57%), and seizures: 3 (43%). All 7 patients (100%) had multiple DSM-5 diagnoses.
Conclusions: These data highlight the need for awareness of the psychiatric comorbidity of BRPS. The findings also underscore the need for further research and emphasize the importance of multidisciplinary collaboration in the prompt assessment, diagnosis, and management of patients presenting with BRPS.
Cuddapah VA, Dubbs HA, Adang L, Kugler SL, McCormick EM, Zolkipli-Cunningham Z, Ortiz-González XR, McCormack S, Zackai E, Licht DJ, Falk MJ, Marsh ED. Understanding the phenotypic spectrum of ASXL-related disease: Ten cases and a review of the literature. Am J Med Genet A. 2021 Jun;185(6):1700-1711. doi: 10.1002/ajmg.a.62156. Epub 2021 Mar 10. PMID: 33751773.
Over the past decade, pathogenic variants in all members of the ASXL family of genes, ASXL1, ASXL2, and ASXL3, have been found to lead to clinically distinct but overlapping syndromes. Bohring-Opitz syndrome (BOPS) was first described as a clinical syndrome and later found to be associated with pathogenic variants in ASXL1. This syndrome is characterized by developmental delay, microcephaly, characteristic facies, hypotonia, and feeding difficulties. Subsequently, pathogenic variants in ASXL2 were found to lead to Shashi-Pena syndrome (SHAPNS) and in ASXL3 to lead to Bainbridge-Ropers syndrome (BRPS). While SHAPNS and BRPS share many core features with BOPS, there also seem to be emerging clear differences. Here, we present five cases of BOPS, one case of SHAPNS, and four cases of BRPS. By adding our cohort to the limited number of previously published patients, we review the overlapping features of ASXL-related diseases that bind them together, while focusing on the characteristics that make each neurodevelopmental syndrome unique. This will assist in diagnosis of these overlapping conditions and allow clinicians to more comprehensively counsel affected families.
Yu KP, Luk HM, Fung JLF, Chung BH, Lo IF. Further expanding the clinical phenotype in Bainbridge-Ropers syndrome and dissecting genotype-phenotype correlation in the ASXL3 mutational cluster regions. Eur J Med Genet. 2021 Jan;64(1):104107. doi: 10.1016/j.ejmg.2020.104107. Epub 2020 Nov 23. PMID: 33242595.
Bainbridge-Ropers syndrome (BRPS) [OMIM#615485] is a neurodevelopmental disorder, characterized by delayed psychomotor development with generalized hypotonia, intellectual disability with poor or absent speech, feeding difficulties, growth failure, specific craniofacial and minor skeletal features. It was firstly reported in 2013 by Bainbridge et al., who observed a group of individuals sharing overlapping features with Bohring-Opitz syndrome which were caused by pathogenic variant in ASXL1, who indeed carried truncating mutations in ASXL3. To date, 33 cases were described in the literature. BRPS is caused by loss-of-function mutations in ASXL3 which are mostly located in two mutational cluster regions (MCR). The exact molecular mechanism of these mutations resulting in the disease phenotype is still uncertain due to the observation of LOF mutations in healthy population. Here, we report four individuals with BRPS carrying de novo LOF mutations in ASXL3, comparing and summarizing the clinical phenotype of all BRPS reported so far. Furthermore, we try to dissect the genotype-phenotype correlation among the two well reported MCRs in all BRPS from the literature.