Homozygous noncanonical splice variant in LSM1 in two siblings with multiple congenital anomalies and global developmental delay
- Volkan Okur1,
- Charles A. LeDuc2,
- Edwin Guzman1,
- Zaheer M. Valivullah3,
- Kwame Anyane-Yeboa1 and
- Wendy K. Chung1,4
- 1Department of Pediatrics, Columbia University, New York, New York 10032, USA;
- 2Department of Pediatrics, Naomi Berrie Diabetes Center, Columbia University, New York, New York 10032, USA;
- 3Center for Mendelian Genomics at the Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;
- 4Department of Medicine, Columbia University, New York, New York 10032, USA
- Corresponding author: wkc15{at}columbia.edu
Abstract
Two siblings, one male and one female, ages 6 and 13 yr old, have similar clinical features of global developmental delay, multiple congenital anomalies affecting the cardiac, genitourinary, and skeletal systems, and abnormal eye movements. Whole-genome sequencing revealed a homozygous splice variant (NM_014462.3:c.231+4A>C) in LSM1 that segregated with the phenotype in the family. LSM1 has a role in pre-mRNA splicing and degradation. Expression studies revealed absence of expression of the canonical isoform in the affected individuals. The Lsm1 knockout mice have a partially overlapping phenotype that affects the brain, heart, and eye. To our knowledge, LSM1 has not been associated with any human disorder; however, the tissue expression pattern, gene constraint, and the similarity of the phenotype in our patients and the knockout mice models suggest it has a role in the development of multiple organ systems in humans.
- bicuspid aortic valve
- bilateral cryptorchidism
- congenital mitral stenosis
- congenital strabismus
- craniofacial asymmetry
- cupped ear
- hydronephrosis
- hydroureter
- inguinal hernia
- intellectual disability, moderate
- intermittent microsaccadic pursuits
- lumbar hemivertebrae
- moderate global developmental delay
- penile hypospadias
- perimembranous ventricular septal defect
- primum atrial septal defect
- triphalangeal thumb
Footnotes
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[Supplemental material is available for this article.]
- Received February 12, 2019.
- Accepted April 8, 2019.
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