TY - JOUR
T1 - Genome-first approach for the characterization of a complex phenotype with combined NBAS and CUL4B deficiency
AU - Ritelli, Marco
AU - Palagano, Eleonora
AU - Cinquina, Valeria
AU - Beccagutti, Federica
AU - Chiarelli, Nicola
AU - Strina, Dario
AU - Hall, Ignacio Fernando
AU - Villa, Anna
AU - Sobacchi, Cristina
AU - Colombi, Marina
N1 - Funding Information:
We thank the patient's family for their collaboration to this study. We thank Prof J.F. Caceres for kindly providing the pcDNA3xFLAGhNBAS vector and the Fazzo Cusan family for its generous support.
Publisher Copyright:
© 2020 Elsevier Inc.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/11
Y1 - 2020/11
N2 - Biallelic variants in neuroblastoma-amplified sequence (NBAS) cause an extremely broad spectrum of phenotypes. Clinical features range from isolated recurrent episodes of liver failure to multisystemic syndrome including short stature, skeletal osteopenia and dysplasia, optic atrophy, and a variable immunological, cutaneous, muscular, and neurological abnormalities. Hemizygous variants in CUL4B cause syndromic X-linked intellectual disability characterized by limitations in intellectual functions, developmental delays in gait, cognitive, and speech functioning, and other features including short stature, dysmorphism, and cerebral malformations. In this study, we report on a 4.5-month-old preterm infant with a complex phenotype mainly characterized by placental-related severe intrauterine growth restriction, post-natal growth failure with spontaneous bone fractures, which led to a suspicion of osteogenesis imperfecta, and lethal bronchopulmonary dysplasia with pulmonary hypertension. Whole exome sequencing identified compound heterozygosity for a known frameshift and a novel missense variant in NBAS and hemizygosity for a known CUL4B nonsense mutation. In vitro functional studies on the novel NBAS missense substitution demonstrated altered Golgi-to-endoplasmic reticulum retrograde vesicular trafficking and reduced collagen secretion, likely explaining part of the patient's phenotype. We also provided a comprehensive overview of the phenotypic features of NBAS and CUL4B deficiency, thus updating the recently emerging NBAS genotype-phenotype correlations. Our findings highlight the power of a genome-first approach for an early diagnosis of complex phenotypes.
AB - Biallelic variants in neuroblastoma-amplified sequence (NBAS) cause an extremely broad spectrum of phenotypes. Clinical features range from isolated recurrent episodes of liver failure to multisystemic syndrome including short stature, skeletal osteopenia and dysplasia, optic atrophy, and a variable immunological, cutaneous, muscular, and neurological abnormalities. Hemizygous variants in CUL4B cause syndromic X-linked intellectual disability characterized by limitations in intellectual functions, developmental delays in gait, cognitive, and speech functioning, and other features including short stature, dysmorphism, and cerebral malformations. In this study, we report on a 4.5-month-old preterm infant with a complex phenotype mainly characterized by placental-related severe intrauterine growth restriction, post-natal growth failure with spontaneous bone fractures, which led to a suspicion of osteogenesis imperfecta, and lethal bronchopulmonary dysplasia with pulmonary hypertension. Whole exome sequencing identified compound heterozygosity for a known frameshift and a novel missense variant in NBAS and hemizygosity for a known CUL4B nonsense mutation. In vitro functional studies on the novel NBAS missense substitution demonstrated altered Golgi-to-endoplasmic reticulum retrograde vesicular trafficking and reduced collagen secretion, likely explaining part of the patient's phenotype. We also provided a comprehensive overview of the phenotypic features of NBAS and CUL4B deficiency, thus updating the recently emerging NBAS genotype-phenotype correlations. Our findings highlight the power of a genome-first approach for an early diagnosis of complex phenotypes.
KW - Bone
KW - CUL4B
KW - Intrauterine growth restriction
KW - NBAS
KW - Osteogenesis imperfecta
KW - Whole exome sequencing
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U2 - 10.1016/j.bone.2020.115571
DO - 10.1016/j.bone.2020.115571
M3 - Article
C2 - 32768688
AN - SCOPUS:85089275034
VL - 140
JO - Bone
JF - Bone
SN - 8756-3282
M1 - 115571
ER -