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Cold Spring Harb Mol Case Stud. 2019 Jun 3;5(3). pii: a004101. doi: 10.1101/mcs.a004101. Print 2019 Jun.

Homozygous noncanonical splice variant in LSM1 in two siblings with multiple congenital anomalies and global developmental delay.

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Department of Pediatrics, Columbia University, New York, New York 10032, USA.
Department of Pediatrics, Naomi Berrie Diabetes Center, Columbia University, New York, New York 10032, USA.
Center for Mendelian Genomics at the Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Department of Medicine, Columbia University, New York, New York 10032, USA.


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

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