2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-A Case of Niemann-Pick Disease Type C from Suspected Uniparental Disomy of Chromosome 18

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This case study describes a 14-year-old female patient with mild intellectual disability and swallowing difficulties. Genetic testing revealed a large region of single nucleotide polymorphism (SNP) homozygosity on chromosome 18, which suggested uniparental isodisomy. The patient was diagnosed with Niemann-Pick Disease Type C (NPC), an autosomal recessive neurodegenerative disorder characterized by the accumulation of cholesterol and glycosphingolipids in various organs. The NPC1 gene, located on chromosome 18, was found to have a homozygous pathogenic variant in the patient. The variant form of NPC associated with this mutation presents with a nonclassical biochemical profile and a later onset of symptoms.<br /><br />UPD of chromosome 18 is rare compared to other chromosomes, but it can have clinical consequences when it affects genes associated with recessive disorders. In this case, the UPD of chromosome 18 contributed to the manifestation of NPC. The patient showed clinical features consistent with NPC, including restricted upward gaze, dysmetria, and coordination difficulties. Treatment with miglustat, an oral inhibitor of glucosylceramide synthase, was initiated to slow disease progression.<br /><br />The patient had a history of seizures, myopia, Hashimoto thyroiditis, and ADHD. She received education through an Individualized Education Plan (IEP) in a special education setting. Additional referrals were made for an abdominal ultrasound to evaluate splenomegaly and palliative care due to the progressive nature of NPC.<br /><br />In conclusion, this case highlights the importance of genetic testing and identifying UPD as a potential contributor to the manifestation of certain disorders. The diagnosis of NPC in this patient was confirmed by the presence of a homozygous pathogenic variant in the NPC1 gene within the region of homozygosity on chromosome 18. Further research and understanding of UPD and its association with specific genetic disorders are needed to improve diagnosis and treatment approaches.

Asset Subtitle

Presenting Author - Allyson Rose, BA; Co-Author - John A. Bernat, MD, PhD;

Meta Tag

Brain/Nervous System

Chromosomal Abnormalities

Clinical Cytogenetics

Cytogenetics

Genetic Testing

Genotype-Phenotype Correlations

Inheritance Patterns

Intellectual disability

Lysosomal Diseases

Pathogenesis

Uniparental Disomy

Co-Author John A. Bernat, MD, PhD

Presenting Author Allyson Rose, BA

Keywords

intellectual disability

swallowing difficulties

genetic testing

Niemann-Pick Disease Type C

autosomal recessive

NPC1 gene

pathogenic variant

UPD of chromosome 18

miglustat

progressive nature of NPC