Discussion

Several studies have reported clinical differences in AS according to genotype. The genetic pattern of AS etiologies is as follows: deletion, approximately 75%; paternal UPD, 1%–2%; point mutation, 5%–10%; imprinting defect, 1%–3%; and unknown, 10%–15%[2]. The deletion type has the highest frequency and is also more likely to show a history of severe medical conditions. Keute et al. in 2021 [8] summarized nine previous studies on differences in clinical symptoms by genotype and reported that problems of seizures (incidence and frequency), mental development, and motor development were all more severe in the deletion type. Several other reports also showed that gastrointestinal reflux disease, scoliosis, and use of nasogastric feeding tube were more frequent in the deletion type [5], [9]. In a study of genetically confirmed AS individuals aged between 18 and 83 years, only 3% were unable to walk [6]. A separate study showed that 98% of adults with AS were able to walk [10]. Many of the non-ambulatory cases reported in [5] and [11] were assumed to be of deletion type.
Compared with published descriptions of deletion type AS cases [4], [5], [9], [11]–[16], the present case is considered particularly severe in motor development and internal complications. We identified only one report of gastrostomy in AS and no report of tracheostomy [7]. The genotype of our patient is of the deletion type, which is regarded as the most profound form of AS but not usually severe enough to require gastrostomy or tracheostomy. However, the clinical course of this case deviated significantly from that of the typical deletion type, and LTS proved necessary to address intractable aspiration. Additionally, aCGH revealed a 19.3 Mb deletion: a magnitude which has not been previously reported.
Prader–Willi syndrome (PWS) is a rare genetic disorder, which, similar to AS, is related to defects on chromosome 15. PWS is associated with a range of complex physical and behavioral problems, usually including hyperphagia. Deletions causing AS and the related PWS generally share a common distal breakpoint (BP3) but differ in their proximal breakpoint (BP1 or BP2) [17]. Accordingly, these deletions can be divided into two main groups: Class I, which span BP1–BP3 (~6 Mb, ~16 genes and various noncoding regions deleted, accounting for about 40% of deletions); and Class II, spanning BP2–BP3 (~5 Mb, ~12 genes and various noncoding regions deleted, ~55% of deletions). Atypical deletions (i.e., Class III and Class IV, accounting for ~5%) may span chromosomal segments longer than Del1 or shorter than Del2 [8], [12], [17], [18]. In both AS and PWS cohorts, patients with Class I deletions are reported to have increased severity of neurodevelopment disorders relative to Class II deletions [12], [15], [17], [19], [20]. Sahoo et al. in 2007 [18] summarized four AS cases with large deletions, including one of 10.68 Mb. All four cases had severe phenotypes, with scores below the average for Class I and Class II deletion children in five key aspects: cognitive abilities, motor skills, communication skills, self-help skills, and socialization skills.” Large deletions are associated with severe phenotypes because of the involvement of several genes (e.g.,APBA2 , TJP1 , TRPM1 , and CHRNA7 ) that may influence phenotypic outcome. The deletion size seen in our patient is larger than any previously reported, and the phenotype is as severe, or more severe, than any previous reports. We consider the unusual deletion length to be a key cause of the atypically profound symptoms and necessity for LTS. The specific clinical manifestations in deletion 15q14 are unknown in this case.
More generally, it may be possible to predict the severity of an individual AS patient’s condition by confirming the deletion size with aCGH. Early follow-up with gastrostomy and tracheostomy in severe AS cases, where clinically indicated, may reduce later medical complications.

Acknowledgments

We would like to thank Professor Saito (Department of Pediatrics, Graduate School of Medical Sciences, Nagoya City University) for advice on appropriate testing based on the clinical course of this case. Written informed consent was obtained from the patient and/or guardians regarding publishing the manuscript, and the report was approved by the Ethics Committee of Iizuka Hospital.

Conflict of Interest Disclosures

The authors declare no conflict of interest.

References

[1] Williams CA, Beaudet AL, Clayton-Smith J, Knoll JH, Kyllerman M, Laan LA, et al. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A. 2006;140(5):413-8.
[2] Buiting K, Williams C, Horsthemke B. Angelman syndrome—insights into a rare neurogenetic disorder. Nat Rev Neurol. 2016;12(10):584-93.
[3] Mertz LG, Christensen R, Vogel I, Hertz JM, Nielsen KB, Grønskov K, et al. Angelman syndrome in Denmark. Birth incidence, genetic findings, and age at diagnosis. Am J Med Genet A. 2013;161(9):2197-203.
[4] Lossie AC, Whitney MM, Amidon D, Dong HJ, Chen P, Theriaque D, et al. Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J Med Genet. 2001;38(12):834-45.
[5] Bindels-de Heus KGCB, Mous SE, Ten Hooven-Radstaake M, van Iperen-Kolk BM, Navis C, Rietman AB, et al. An overview of health issues and development in a large clinical cohort of children with Angelman syndrome. Am J Med Genet A. 2020;182(1):53-63.
[6] den Besten I, de Jong RF, Geerts-Haages A, Bruggenwirth HT, Koopmans M; ENCORE Expertise Center for AS 18+, et al. Clinical aspects of a large group of adults with Angelman syndrome. Am J Med Genet A. 2021;185(1):168-81.
[7] Khan N, Cabo R, Tan WH, Tayag R, Bird LM. Healthcare burden among individuals with Angelman syndrome: findings from the Angelman Syndrome Natural History Study. Mol Genet Genomic Med. 2019;7(7):e00734.
[8] Keute M, Miller MT, Krishnan ML, Sadhwani A, Chamberlain S, Thibert RL, et al. Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment. Mol Psychiatry. 2021;26(7):3625-33.
[9] Glassman LW, Grocott OR, Kunz PA, Larson AM, Zella G, Ganguli K, et al. Prevalence of gastrointestinal symptoms in Angelman syndrome. Am J Med Genet A. 2017;173(10):2703-9.
[10] Prasad A, Grocott O, Parkin K, Larson A, Thibert RL. Angelman syndrome in adolescence and adulthood: a retrospective chart review of 53 cases. Am J Med Genet A. 2018;176(6):1327-34
[11] Moncla A, Malzac P, Voelckel MA, Auquier P, Girardot L, Mattei MG, et al. Phenotype-genotype correlation in 20 deletion and 20 non-deletion Angelman syndrome patients. Eur J Hum Genet. 1999;7(2):131-9.
[12] Varela MC, Kok F, Otto PA, Koiffmann CP. Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects. Eur J Hum Genet. 2004;12:987–92.
[13] Luk HM, Lo IFM. Angelman syndrome in Hong Kong Chinese: a 20 years’ experience. Eur J Med Genet. 2016;59(6-7):315-9.
[14] Shaaya EA, Grocott OR, Laing O, Thibert RL. Seizure treatment in Angelman syndrome: a case series from the Angelman Syndrome Clinic at Massachusetts General Hospital. Epilepsy Behav. 2016;60:138-41.
[15] Sahoo T, Peters SU, Madduri NS, Glaze DG, German JR, Bird LM, et al. Microarray based comparative genomic hybridization testing in deletion bearing patients with Angelman syndrome: genotype-phenotype correlations. J Med Genet. 2006;43:512-6.
[16] Gentile JK, Tan WH, Horowitz LT, Bacino CA, Skinner SA, Barbieri-Welge R, et al. A neurodevelopmental survey of Angelman syndrome with genotype-phenotype correlations. J Dev Behav Pediatr. 2010;31(7):592-601.
[17] Cafferkey M, Ahn JW, Flinter F, Ogilvie C. Phenotypic features in patients with 15q11.2(BP1-BP2) deletion: further delineation of an emerging syndrome. Am J Med Genet A. 2014;164A(8):1916-22.
[18] Sahoo T, Bacino CA, German JR, Shaw CA, Bird LM, Kimonis V, et al. Identification of novel deletions of 15q11q13 in Angelman syndrome by array-CGH: molecular characterization and genotype-phenotype correlations. Eur J Hum Genet. 2007;15(9):943-9.
[19] Butler MG, Bittel DC, Kibiryeva N, Talebizadeh Z, Thompson T. Behavioral differences among subjects with Prader-Willi syndrome and type I or type II deletion and maternal disomy. Pediatrics. 2004;113:565-73.
[20] Hartley SL, Maclean Jr. WE, Butler MG, Zarcone J, Thompson T. Maladaptive behaviors and risk factors among the genetic subtypes of Prader-Willi syndrome. Am J Med Genet A. 2005;136A:140-5.