Phenotype from SAMD9 Mutation at 7p21.2 Appears Attenuated by Novel Compound Heterozygous Variants at RUNX2 and SALL1.

Samuel H Wood,E Scott Sills

doi:10.1055/s-0041-1740018

Abstract

Sterile α motif domain-containing protein 9 (SAMD9) is a regulatory protein centrally involved in cell proliferation and apoptosis. Mapped to 7p21.2, 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 multiexon 3′ terminal duplication of RUNX2 not previously encountered is also reported. This is the first known phenotype assessment for an 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 coronavirus disease 2019 (COVID-19) illness. Individually, disruption in SAMD9, RUNX2, or SALL1 would be expected to give a bleak prognosis. However, this variant convergence appears to dampen severe pathology perhaps by cross-gene silencing of effects normally deleterious when such changes occur alone.

Highlights

Mutations in SAMD9 are usually recognized early in life, as adaptive immune response impairment leads to chronic childhood infections and high mortality by age 10.1,2 SAMD9 maps to chromosome 7q21.2, a region frequently deleted in myeloid malignancies
Narumi et al[3] were the first to implicate germline missense SAMD9 mutations as causative for a rare condition known as MIRAGE syndrome
Occurrence of SAMD9, RUNX2, and Spalt like transcription factor 1 gene (SALL1) mutation in humans is rare and information on these events mainly comes from small series or case reports

Summary

Introduction

Mutations in SAMD9 (sterile α motif domain-containing protein 9) are usually recognized early in life, as adaptive immune response impairment leads to chronic childhood infections and high mortality by age 10.1,2 SAMD9 maps to chromosome 7q21.2, a region frequently deleted in myeloid malignancies. Compound Variants in SAMD9, RUNX2, SALL1 Sills, Wood genital anomaly, and enteropathy) Such mutations were later identified in $18% of inherited bone marrow failure and myelodysplasia cases.[4] Regarding RUNX2, $200 different mutations are known and most are seen with cleidocranial dysplasia, an autosomal dominant skeletal disorder including clavicular dysmorphia, increased head circumference, large fontanels, dental anomalies, short stature, and sometimes hand malformations.[5] Spalt like transcription factor 1 gene (SALL1) modulates onset and progression of human tumors, with variants known to be associated with Townes-Brocks syndrome (i.e., anal, renal, limb, and ear anomalies).[6,7] While disruptions in SAMD9, RUNX2, and SALL1 have each been encountered separately, this report is the first to present data on simultaneous variants in all three.

Genomic Methodology

Discussion