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Methods

• The ATP8A2 gene (MIM# 605870) is highly expressed in the retina, spinal cord, brain, and testis (Cacciagli et al., 2010; Zhu et al., 2012).

• Previously reported cases with ATP8A2 variants include compound heterozygous and homozygous variants in patients with intellectual disability, movement disorders, optic atrophy, and hypotonia.

• We describe four unrelated patients ranging in age from one to nine years with clinical features consistent with those previously described identified via Exome Sequencing (ES). A fifth patient was not included in analysis due to lack of consent. A sixth patient initially identified via GeneMatcher was not included due to lack of clinical information.

• Exome sequencing was performed on exon targets isolated by capture using the Agilent SureSelect Human All Exon V4 (50 Mb) or Clinical Research Exome kit.

• The sequencing methodology and variant interpretation protocol has been previously described.3

• Identified sequence changes of interest were confirmed in all members of the family on whom biospecimens were available by di-deoxy DNA sequence analysis or an alternative method.

Background

Results

Conclusions

• Reported cases with ATP8A2 variants include compound heterozygous and homozygous variants in patients with intellectual disability, movement disorders, optic atrophy, and hypotonia.

• Movement disorders in our patients included: chorea in four patients, dystonia in three patients, ataxia in two patients, and tremor in one patient. Additional features reported in our patients include brain abnormalities (periventricular heterotopia, prominent ventricles) in one patient, dysmorphic features, hypermobility, sleep abnormalities, and seizures reported in a single patient. Detailed clinical findings are listed in Table 1.

• The variants identified ranged from missense, splicing, intragenic deletions, and frameshift.

• Patient 2 was noted to have severe optic nerve atrophy at 4-1/2 years old (Figure 1).

• The findings presented in this case series add to the already described  ATP8A2-related disorder by further characterizing this autosomal recessive neurodegenerative disorder molecularly and phenotypically.

• Main phenotypic characteristics identified in patients with homozygous and heterozygous variants included intellectual disability, movement disorders, optic atrophy, and hypotonia.

1. Cacciagli et al. (2010) European Journal Of Human Genetics : Ejhg 18 (12):1360-3 (PMID: 20683487)

2. Zhu et al. (2012) P Lo S Genetics 8 (8):e1002853 (PMID: 22912588)

3. Tanaka et al. (2015) Am. J. Hum. Genet. 97 (3):457-64 (PMID: 26299366)

References

FURTHER CLINICAL AND MOLECULAR CHARACTERIZATION OF THE NOVEL AUTOSOMAL RECESSIVE NEURODEGENERATIVE DISORDER RELATED TO THE ATP8A2 GENEA. Telegrafi, MS, CGC1; A. Singleton, ScM, MPH, CGC1; M. Cho, ScM, CGC1; C. Mignot, MD, PhD2,3,4; D. Doummar, MD5; C. Nava MD, PhD6; B. Keren, MD, PhD7; A. Schreiber, MS, LGC8; H. McMillan, MD, MSc, FRCPC, FAAN9; G. Yoon, MD, FRCPC, FCCMG10; L. Velsher, MD CM, FRCPC, FACMG11; I. Thompson, MSc11; J. Griffin, MS, CGC12; A. Asamoah, MD, PhD12; K. Retterer, MS1; C. Forster, BA1; D. McKnight, PhD, FACMG1; L. Vincent, PhD, FACMG1; G. Douglas, PhD, FACMG1; R. Person, PhD, FACMG1; L. Henderson, PhD, FACMG1; M.J. Guillen Sacoto, MD1; H. McLaughlin, PhD, FACMG1; J. Juusola, PhD, FACMG1

1GeneDx, Gaithersburg, MD, United States, 2Assistance Publique Hôpitaux de Paris, Département de Génétique, Groupe Hospitalier, Pitié-Salpêtrière, Paris, France, 3Centre de Référence Déficiences Intellectuelles de Causes Rares, GH Pitié Salpêtrière, Paris, France, 4Groupe de Recherche Clinique UPMC Déficience Intellectuelle de Causes Rares et Autisme GH Pitié-Salpêtrière, Paris France, 5Service de Neuropédiatrie, Hôpital Armand-Trousseau, Paris, France, 6Centre de Génétique Moléculaire et Chromosomique Groupe Hospitalier Pitié-Salpêtrière, Paris, France, 7Assistance Publique Hôpitaux de Paris, Département de Génétique, Groupe Hospitalier, Pitié-Salpêtrière, Paris, France, 8Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, 9Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada, 10The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada, 11North York General Hospital, Toronto, ON, Canada, 12 Department of Pediatrics, Weisskopf Child Evaluation Center, University of Louisville School of Medicine, Louisville, KY, United States

A. Fundoscopic examination at 4-1/2 years old reveals severe bilateral optic atrophy. Retina otherwise appears normal.

B. Optical coherence tomography reveals relatively thin retinal nerve fiber layer with grossly normal retinal architecture otherwise.

Table 1. Summary of Significant Clinical Features for our Patient Cohort

Clinical Features Patient 1 Patient 2 Patient 3 Patient 4

Age (yrs) 9 5 7 1

Developmental delay / Intellectual disability

X X X X

Cerebellar ataxia X

Severe hypotonia X X X X

Chorea X X X X

Optic atrophy X X X

Dystonia X X X

Tremor X

Brain abnormalities X

ATP8A2 variant D428A / c.2211+1G>A

c.1185+5G>A/ exon 28-33 del

K429M (homozygous)

c.1787delA / c.321+3_321+ 8delAATGGT

Figure 1. Opthalmological Studies (Patient 2)