2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Cortical Brain Malformations in Two Siblings with Poretti Boltshauser Syndrome: A Possible Phenotype Expansion

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Researchers from the University of Utah/Primary Children’s Hospital have identified potential phenotypic expansion of Poretti-Boltshauser syndrome (PBS), a rare genetic disease, in two siblings with compound heterozygous variants in the LAMA1 gene. PBS is characterized by cerebellar dysplasia and cysts, ataxia, ophthalmologic problems, and developmental delays. However, the two siblings also exhibited malformations of cortical development, specifically frontotemporal polymicrogyria and cobblestone lissencephaly, which are not established phenotypes of PBS.<br /><br />The patients presented with speech and motor delays, as well as typical cerebellar findings of PBS. EEG results were abnormal in one sibling, but neither had confirmed seizures. The researchers confirmed adequate sequencing coverage for other brain malformation genes, excluding other conditions associated with similar cerebellar dysphasia and cysts. Previous literature suggested that lack of supratentorial abnormalities distinguished PBS from these conditions.<br /><br />However, the two siblings in this study, along with a previously reported case, demonstrate supratentorial abnormalities on MRI brain imaging, suggesting a possible phenotypic expansion of PBS. The presence of cortical abnormalities, including lissencephaly and polymicrogyria, may be part of the PBS spectrum and not an exclusionary feature as previously thought. The researchers emphasize that the risk of seizures and developmental delay is increased in PBS patients with cortical abnormalities.<br /><br />Genetic testing revealed compound heterozygous variants in the LAMA1 gene in both siblings. The variants were predicted to be pathogenic, resulting in truncating or loss of function of the LAMA1 protein. Homozygous or compound heterozygous pathogenic variants in LAMA1 are associated with autosomal recessive PBS.<br /><br />These findings highlight the importance of establishing phenotypic expansion for LAMA1, as it impacts clinical diagnosis, prognosis, and accurate recurrence risk genetic counseling for affected families.

Asset Subtitle

Co-Author - Cassie Turnage, MD; Presenting Author - Rachel Palmquist, MS, CGC; Co-Author - Melissa Wright, MD;

Meta Tag

Brain/Nervous System

Cognitive Disorders

Congenital Anomaly

Counseling

Malformation

Co-Author Cassie Turnage, MD

Co-Author Melissa Wright, MD

Presenting Author Rachel Palmquist, MS, CGC

Keywords

Poretti-Boltshauser syndrome

genetic disease

LAMA1 gene

cerebellar dysplasia

cysts

frontotemporal polymicrogyria

cobblestone lissencephaly

speech delays

motor delays

seizures