Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Phenotype from SAMD9 Mutation at 7p21.1 Appears Attenuated by Novel Compound Heterozygous Variants at RUNX2 and SALL1

Version 1 : Received: 25 September 2021 / Approved: 28 September 2021 / Online: 28 September 2021 (08:36:59 CEST)

How to cite: Sills, E.S.; Wood, S.H. Phenotype from SAMD9 Mutation at 7p21.1 Appears Attenuated by Novel Compound Heterozygous Variants at RUNX2 and SALL1. Preprints 2021, 2021090458 (doi: 10.20944/preprints202109.0458.v1). Sills, E.S.; Wood, S.H. Phenotype from SAMD9 Mutation at 7p21.1 Appears Attenuated by Novel Compound Heterozygous Variants at RUNX2 and SALL1. Preprints 2021, 2021090458 (doi: 10.20944/preprints202109.0458.v1).

Abstract

Sterile alpha motif domain-containing protein 9 (SAMD9) is a regulatory protein centrally involved in cell proliferation and apoptosis. Mapped to 7p21.1, variants in SAMD9 have been reported in <50 pediatric cases worldwide, typically with early lethality. Germline gain-of-function SAMD9 variants are associated with MIRAGE Syndrome (myelodysplasia, infection, restricted growth, adrenal hypoplasia, genital anomalies, and enteropathy). Spalt like transcription factor 1 (SALL1) is a zinc finger transcriptional repressor located at 16q12.1 where only two transcript variants in SALL1 are known. RUNX2 (6p21.1) encodes a nuclear protein with a Runt DNA-binding domain critical for osteoblastic differentiation, skeletal morphogenesis, and serves as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. RUNX2 and SALL1 are thus both ‘master regulators’ of tissue organization and embryo development. Here, we describe exome sequencing and copy number variants in two previously unknown mutations—R824Q in SAMD9, and Q253H in SALL1. A new multiexon 3’ terminal duplication in RUNX2 is also reported. This is the first known phenotype characterization for the intersection of all three variants in a healthy 46,XX adult. Focusing on developmental progress, ultrastructural renal anatomy, and selected reproductive aspects, we describe this unique genotype diagnosed incidentally during Covid-19 illness. Individual disruption in SAMD9, RUNX2, or SALL1 would be expected to give a bleak prognosis. However, the convergence discovered here appears to dampen severe pathology, perhaps by cross-gene silencing of effects normally deleterious when such changes occur alone.

Keywords

SAMD9; RUNX2; SALL1; ovarian anatomy; renal structure

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