A neurodevelopmental disorder caused by a novel de novo SVA insertion in exon 13 of the SRCAP gene

Boxun Zhao; Jill A Madden; Jasmine Lin; Gerard T Berry; Monica H Wojcik; Xuefang Zhao; Harrison Brand; Michael Talkowski; Eunjung Alice Lee; Pankaj B Agrawal

doi:10.1038/s41431-022-01137-3

A neurodevelopmental disorder caused by a novel de novo SVA insertion in exon 13 of the SRCAP gene

Eur J Hum Genet. 2022 Sep;30(9):1083-1087. doi: 10.1038/s41431-022-01137-3. Epub 2022 Jun 30.

Authors

Boxun Zhao^{1

2

3}, Jill A Madden^{1

2}, Jasmine Lin^{1

2

4}, Gerard T Berry^{1

2}, Monica H Wojcik^{1

2

3

4}, Xuefang Zhao^{5

6

7}, Harrison Brand^{5

6

7}, Michael Talkowski^{5

6

7}, Eunjung Alice Lee^{8

9

10}, Pankaj B Agrawal^{11

12

13

14}

Affiliations

¹ Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
² Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA.
³ The Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁴ Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
⁵ Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁶ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁷ Department of Neurology, Harvard Medical School, Boston, MA, USA.
⁸ Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. [email protected].
⁹ Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA. [email protected].
¹⁰ The Broad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected].
¹¹ Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. [email protected].
¹² Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA. [email protected].
¹³ The Broad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected].
¹⁴ Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. [email protected].

Abstract

Pathogenic variants in the SRCAP (SNF2-related CREBBP activator protein) gene, which encodes a chromatin-remodeling ATPase, cause neurodevelopmental disorders including Floating Harbor syndrome (FLHS). Here, we report the discovery of a de novo transposon insertion in SRCAP exon 13 from trio genome sequencing in a 28-year-old female with failure to thrive, developmental delay, mood disorder and seizure disorder. The insertion was a full-length (~2.8 kb), antisense-oriented SVA insertion relative to the SRCAP transcript, bearing a 5' transduction and hallmarks of target-primed reverse transcription. The 20-bp 5' transduction allowed us to trace the source SVA element to an intron of a long non-coding RNA on chromosome 12, which is highly expressed in testis. RNA sequencing and qRT-PCR confirmed significant depletion of SRCAP expression and low-level exon skipping in the proband. This case highlights a novel disease-causing structural variant and the importance of transposon analysis in a clinical diagnostic setting.

Publication types

Case Reports
Research Support, N.I.H., Extramural

MeSH terms

Abnormalities, Multiple* / genetics
Adenosine Triphosphatases / genetics
Adult
Craniofacial Abnormalities* / genetics
Exons
Female
Heart Septal Defects, Ventricular* / genetics
Humans
Male
Neurodevelopmental Disorders* / diagnosis
Neurodevelopmental Disorders* / genetics

Substances

Adenosine Triphosphatases
SRCAP protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding