TY - JOUR
T1 - Biallelic ASCC1 variants including a novel intronic variant result in expanded phenotypic spectrum of spinal muscular atrophy with congenital bone fractures 2 (SMABF2)
AU - Rosano, Kristen K.
AU - Wegner, Daniel J.
AU - Shinawi, Marwan
AU - Baldridge, Dustin
AU - Bucelli, Robert C.
AU - Dahiya, Sonika
AU - White, Frances V.
AU - Willing, Marcia C.
AU - McAllister, William
AU - Taft, Ryan J.
AU - Bluske, Krista
AU - Buchanan, Amanda
AU - Cole, Francis Sessions
AU - Wambach, Jennifer A.
N1 - Funding Information:
The authors thank Katie Shields, B.A., of Washington University School of Medicine for her assistance with sample acquisition and study enrollment. The authors thank the Genome Aggregation Database (gnomad.broadinstitute.org), a resource developed by an international coalition of investigators with the goal of aggregating and harmonizing exome and genome sequencing data from a wide variety of large-scale sequencing projects and providing summary data available to the wider scientific community. This work was supported by grants from the National Institutes of Health (K12 HL120002 (F. Sessions Cole), R33 HL120760 (F. Sessions Cole), R01 HL149853 (Jennifer A. Wambach) and the Children's Discovery Institute (F. Sessions Cole and Jennifer A. Wambach).
Funding Information:
The authors thank Katie Shields, B.A., of Washington University School of Medicine for her assistance with sample acquisition and study enrollment. The authors thank the Genome Aggregation Database ( gnomad.broadinstitute.org ), a resource developed by an international coalition of investigators with the goal of aggregating and harmonizing exome and genome sequencing data from a wide variety of large‐scale sequencing projects and providing summary data available to the wider scientific community. This work was supported by grants from the National Institutes of Health (K12 HL120002 (F. Sessions Cole), R33 HL120760 (F. Sessions Cole), R01 HL14983 (Jennifer A. Wambach) and the Children's Discovery Institute (F. Sessions Cole and Jennifer A. Wambach).
Publisher Copyright:
© 2021 Wiley Periodicals LLC.
PY - 2021/7
Y1 - 2021/7
N2 - Spinal muscular atrophy with congenital bone fractures 2 (SMABF2), a type of arthrogryposis multiplex congenita (AMC), is characterized by congenital joint contractures, prenatal fractures of long bones, and respiratory distress and results from biallelic variants in ASCC1. Here, we describe an infant with severe, diffuse hypotonia, congenital contractures, and pulmonary hypoplasia characteristic of SMABF2, with the unique features of cleft palate, small spleen, transverse liver, and pulmonary thromboemboli with chondroid appearance. This infant also had impaired coagulation with diffuse petechiae and ecchymoses which has only been reported in one other infant with AMC. Using trio whole genome sequencing, our proband was identified to have biallelic variants in ASCC1. Using deep next generation sequencing of parental cDNA, we characterized alteration of splicing encoded by the novel, maternally inherited ASCC1 variant (c.297-8 T > G) which provides a mechanism for functional pathogenicity. The paternally inherited ASCC1 variant is a rare nonsense variant (c.466C > T; p.Arg156*) that has been previously identified in one other infant with AMC. This report extends the phenotypic characteristics of ASCC1-associated AMC (SMABF2) and describes a novel intronic variant that partially disrupts RNA splicing.
AB - Spinal muscular atrophy with congenital bone fractures 2 (SMABF2), a type of arthrogryposis multiplex congenita (AMC), is characterized by congenital joint contractures, prenatal fractures of long bones, and respiratory distress and results from biallelic variants in ASCC1. Here, we describe an infant with severe, diffuse hypotonia, congenital contractures, and pulmonary hypoplasia characteristic of SMABF2, with the unique features of cleft palate, small spleen, transverse liver, and pulmonary thromboemboli with chondroid appearance. This infant also had impaired coagulation with diffuse petechiae and ecchymoses which has only been reported in one other infant with AMC. Using trio whole genome sequencing, our proband was identified to have biallelic variants in ASCC1. Using deep next generation sequencing of parental cDNA, we characterized alteration of splicing encoded by the novel, maternally inherited ASCC1 variant (c.297-8 T > G) which provides a mechanism for functional pathogenicity. The paternally inherited ASCC1 variant is a rare nonsense variant (c.466C > T; p.Arg156*) that has been previously identified in one other infant with AMC. This report extends the phenotypic characteristics of ASCC1-associated AMC (SMABF2) and describes a novel intronic variant that partially disrupts RNA splicing.
KW - AMC
KW - ASCC1
KW - SMABF2
KW - arthrogryposis
KW - arthrogryposis multiplex congenita
KW - spinal muscular atrophy with congenital bone fractures 2
UR - http://www.scopus.com/inward/record.url?scp=85105207886&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.62219
DO - 10.1002/ajmg.a.62219
M3 - Article
C2 - 33931933
AN - SCOPUS:85105207886
SN - 1552-4825
VL - 185
SP - 2190
EP - 2197
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 7
ER -