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• Milder phenotype in a boy with Bainbridge Ropers Syndrome and ASXL3 mutation. Expanding the phenotypic spectrum
  Neeta Lakhani, Pradeep Vasudevan, Chaya Kapugama and Deciphering Developmental Disorders Study DDD Study
  Published on: 8 November 2017

• Published on: 8 November 2017

  Milder phenotype in a boy with Bainbridge Ropers Syndrome and ASXL3 mutation. Expanding the phenotypic spectrum

  • Neeta Lakhani, Specialty Registrar in Clinical Genetics Leicester Royal Infirmary
  • Other Contributors:
    • Pradeep Vasudevan, Head of Service, Consultant in Clinical Genetics and Honorary Professor at University of Leicester
    • Chaya Kapugama, Specialty Registrar (ST5) in Psychiatry of Intellectual Disability
    • Deciphering Developmental Disorders Study DDD Study, Welcome Trust Sanger Institute

  We read with interest the case series of 12 patients with loss-of-function denovo heterozygous mutations in ASXL3, reported by Balasubramanian et al in August 2017. We want to report on a further case of Bainbridge – Ropers Syndrome (BRS) seen in our department. The purpose of this letter is two-fold. The first is to report on the mild features of BRS and the second is to expand the spectrum of features in BRS reiterating that all cases may not have severe features.

  The proband is now 7 years old who first presented to the genetic services at the age of 3 years with global developmental delay and epilepsy. He is the first child of non-consanguineous healthy parent of Indian heritage. There is no family history of learning difficulties, autism or developmental delay.

  He was born after a normal pregnancy by LSCS for prolonged labour with a birth weight of 2.9kg at term. He started sitting independently at 16 months and walking at 22 months. He has speech and language delay. He initially presented with 2 episodes of febrile convulsions; the first lasting 1 minute and second 10 minutes, at 3 and a half years of age. He then went on to develop tonic- clonic seizures thereafter all requiring hospital admission. He was recruited to the deciphering development disorder project (DDD) and on whole exome sequencing detected two variants in ASXL3 and DMD gene respectively.

  This variant is predicted to cause a frameshift mutation resulting in a premature terminat...

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  We read with interest the case series of 12 patients with loss-of-function denovo heterozygous mutations in ASXL3, reported by Balasubramanian et al in August 2017. We want to report on a further case of Bainbridge – Ropers Syndrome (BRS) seen in our department. The purpose of this letter is two-fold. The first is to report on the mild features of BRS and the second is to expand the spectrum of features in BRS reiterating that all cases may not have severe features.

  The proband is now 7 years old who first presented to the genetic services at the age of 3 years with global developmental delay and epilepsy. He is the first child of non-consanguineous healthy parent of Indian heritage. There is no family history of learning difficulties, autism or developmental delay.

  He was born after a normal pregnancy by LSCS for prolonged labour with a birth weight of 2.9kg at term. He started sitting independently at 16 months and walking at 22 months. He has speech and language delay. He initially presented with 2 episodes of febrile convulsions; the first lasting 1 minute and second 10 minutes, at 3 and a half years of age. He then went on to develop tonic- clonic seizures thereafter all requiring hospital admission. He was recruited to the deciphering development disorder project (DDD) and on whole exome sequencing detected two variants in ASXL3 and DMD gene respectively.

  This variant is predicted to cause a frameshift mutation resulting in a premature termination codon in exon 12 of ASXL3. There are no other reports of this variant in any databases or in the published literature. Loss of function variant in ASXL3 have been reported in patients with Bainbridge – Ropers Syndrome (OMIM #615485)

  Our patient was also found to have another variant – DMD C 726a>t p(Gln242His). This variant is predicted to replace the amino acid Glutamine with Histidine at position 242 in the dystrophin protein. There are no reports of this variant in any databases or in the published literature. The protein prediction algorithm within the Alamut variant analysis software package (v2.7.2) do not predict an effect on protein function and there is no evidence of an alteration to splicing. Loss of function variants in the DMD cause XP21 dystrophionopathy, however most pathogenic variants lead to a truncated protein and missense variants in DMD are usually well tolerated. Our proband has a normal creatinine kinase level and is showing no features of Xp21 dystrophionopathy therefore it is unlikely that this variant is pathogenic.

  At 7 years of age he can talk in sentences, he walks independently and attends special school. He is still in nappies and there are no concerns regarding his feeding and sleeping. His height and weight are on the 91st centile and the head circumference on the 2nd centile. His facial features consist of long face, arched eyebrows, synophrys and prominent columella.

  In conclusion we present a boy with milder features of BRS. He did not have the characteristic features of severe muscular hypotonia with feeding difficulties, significant speech and motor delay with epilepsy. He has mild developmental delay with some characteristic facial features with a denovo pathogenic frameshift mutation in exon 12 of ASXL3. Our case illustrates that the clinical features in BRS can show wide variation, which can present with milder features of developmental delay, facial dysmorphism and premature protein truncation.

  References:

  Balasubramanian M, Willoughby J, Fry AE, Weber A, Firth HV, Deshpande C, Berg JN, Chandler K, Metcalfe KA, Lam W, et al. Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature. J Med Genet. 2017 Aug; 54(8):537-543.

  Hori I, Miya F, Ohashi K, Negishi Y, Hattori A, Ando N, Okamoto N, Kato M, Tsunoda T, Yamasaki M, et al Novel splicing mutation in the ASXL3 gene causing Bainbridge-Ropers syndrome. Am J Med Genet A. 2016 Jul; 170(7):1863-7.

  Kuechler A, Czeschik JC, Graf E, Grasshoff U, Hüffmeier U, Busa T, Beck-Woedl S, Faivre L, Rivière JB, Bader I, et al. Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition. Eur J Hum Genet. 2017 Feb; 25(2):183-191.

  Srivastava A, Ritesh KC, Tsan YC, Liao R, Su F, Cao X, Hannibal MC, Keegan CE, Chinnaiyan AM, Martin DM, Bielas SL. De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome. Hum Mol Genet. 2016 Feb 1;25(3):597-608.

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  Conflict of Interest:
  None declared.

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