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An emerging ribosomopathy affecting the skeleton due to biallelic variations in NEPRO
Author(s) -
Narayanan Dhanya L.,
Shukla Anju,
Kausthubham Neethukrishna,
Bhavani Gandham S.,
Shah Hitesh,
Mortier Geert,
Girisha Katta M.
Publication year - 2019
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.61267
Subject(s) - missense mutation , phenotype , genetics , brachydactyly , dysplasia , camptodactyly , biology , proband , hypertrichosis , exome sequencing , short stature , hypotrichosis , microcephaly , mutation , endocrinology , evolutionary biology , gene
Cartilage hair hypoplasia (CHH), anauxetic dysplasia 1, and anauxetic dysplasia 2 are rare metaphyseal dysplasias caused by biallelic pathogenic variants in RMRP and POP1 , which encode the components of RNAse‐MRP endoribonuclease complex (RMRP) in ribosomal biogenesis pathway. Nucleolus and neural progenitor protein (NEPRO), encoded by NEPRO ( C3orf17 ), is known to interact with multiple protein subunits of RMRP. We ascertained a 6‐year‐old girl with skeletal dysplasia and some features of CHH. RMRP and POP1 did not harbor any causative variant in the proband. Parents‐child trio exomes revealed a candidate biallelic variant, c.435G>C, p.(Leu145Phe) in NEPRO . Two families with four affected individuals with skeletal dysplasia and a homozygous missense variant, c.280C>T, p.(Arg94Cys) in NEPRO , were identified from literature and their published phenotype was compared in detail to the phenotype of the child we described. All the five affected individuals have severe short stature, brachydactyly, skin laxity, joint hypermobility, and joint dislocations. They also have short metacarpals, broad middle phalanges, and metaphyseal irregularities. Protein modeling and stability prediction showed that the mutant protein has decreased stability. Both the reported variants are in the same domain of the protein. Our report delineates the clinical and radiological characteristics of an emerging ribosomopathy caused by biallelic variants in NEPRO .