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

Sterile α 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...

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Autores principales:	E. Scott Sills, Samuel H. Wood
Formato:	article
Lenguaje:	EN
Publicado:	Georg Thieme Verlag KG 2021
Materias:	samd9 runx2 sall1 phenotype renal structure Genetics QH426-470 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/637ec5b7a7504896a1d973af0cb12458
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spelling	oai:doaj.org-article:637ec5b7a7504896a1d973af0cb124582021-12-04T00:22:10ZPhenotype from SAMD9 Mutation at 7p21.1 Appears Attenuated by Novel Compound Heterozygous Variants at RUNX2 and SALL12699-940410.1055/s-0041-1740018https://doaj.org/article/637ec5b7a7504896a1d973af0cb124582021-12-01T00:00:00Zhttp://www.thieme-connect.de/DOI/DOI?10.1055/s-0041-1740018https://doaj.org/toc/2699-9404Sterile α 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 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.E. Scott SillsSamuel H. WoodGeorg Thieme Verlag KGarticlesamd9runx2sall1phenotyperenal structureGeneticsQH426-470Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENGlobal Medical Genetics (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	samd9 runx2 sall1 phenotype renal structure Genetics QH426-470 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	samd9 runx2 sall1 phenotype renal structure Genetics QH426-470 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 E. Scott Sills Samuel H. Wood Phenotype from SAMD9 Mutation at 7p21.1 Appears Attenuated by Novel Compound Heterozygous Variants at RUNX2 and SALL1
description	Sterile α 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 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.
format	article
author	E. Scott Sills Samuel H. Wood
author_facet	E. Scott Sills Samuel H. Wood
author_sort	E. Scott Sills
title	Phenotype from SAMD9 Mutation at 7p21.1 Appears Attenuated by Novel Compound Heterozygous Variants at RUNX2 and SALL1
title_short	Phenotype from SAMD9 Mutation at 7p21.1 Appears Attenuated by Novel Compound Heterozygous Variants at RUNX2 and SALL1
title_full	Phenotype from SAMD9 Mutation at 7p21.1 Appears Attenuated by Novel Compound Heterozygous Variants at RUNX2 and SALL1
title_fullStr	Phenotype from SAMD9 Mutation at 7p21.1 Appears Attenuated by Novel Compound Heterozygous Variants at RUNX2 and SALL1
title_full_unstemmed	Phenotype from SAMD9 Mutation at 7p21.1 Appears Attenuated by Novel Compound Heterozygous Variants at RUNX2 and SALL1
title_sort	phenotype from samd9 mutation at 7p21.1 appears attenuated by novel compound heterozygous variants at runx2 and sall1
publisher	Georg Thieme Verlag KG
publishDate	2021
url	https://doaj.org/article/637ec5b7a7504896a1d973af0cb12458
work_keys_str_mv	AT escottsills phenotypefromsamd9mutationat7p211appearsattenuatedbynovelcompoundheterozygousvariantsatrunx2andsall1 AT samuelhwood phenotypefromsamd9mutationat7p211appearsattenuatedbynovelcompoundheterozygousvariantsatrunx2andsall1
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Phenotype from SAMD9 Mutation at 7p21.1 Appears Attenuated by Novel Compound Heterozygous Variants at RUNX2 and SALL1

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