Abstract
We describe the case of a seven-year-old female patient who presented in our service with severe developmental delay, intellectual disability, facial dysmorphism, and femur fracture, observed in the context of very low bone mineral density. Array-based single nucleotide polymorphism (SNP array) analysis identified a 113 kb duplication involving the morbid OMIM genes: ANKRD11 (exon1), RPL13, and PGN genes. ANKRD11 deletions are frequently described in association with KBG syndrome, the duplications being less frequent (one case described before). The exome sequencing was negative for pathogenic variants or of uncertain significance in genes possibly associated with this phenotype. The patient presented subtle signs of KBG syndrome. It is known that the phenotype of KBG syndrome has a wide clinical spectrum, this syndrome being often underdiagnosed due to overlapping features with other conditions, also characterized by multiple congenital anomalies and intellectual disability. The particularity of this case is represented by the very low bone mineral density in a patient with 16q24.3 duplication. ANKRD11 haploinsufficiency is known to be associated with skeletal involvement, such as short stature, or delayed bone age. An effect on bone density has been observed only in experimental studies on mice with induced missense mutations in the ANKRD11 gene. This CNV also involved the duplication of the very conserved RPL13 gene, which could have a role for the skeletal phenotype of this patient, knowing the high level of gene expression in bone tissue and also the association with spondyloepimetaphyseal dysplasia Isidor Toutain type, in case of splicing mutations.
Highlights
The copy number variants (CNVs) involving 16q24.3 region are often associated with KBG syndrome (OMIM 148050), which is a rare genetic condition with autosomal dominant inheritance, firstly described by Hermann in 1975 [1]
OMIM genes: ANKRD11, RPL11 and PGN (Figure 2). This duplication event involves the ANKRD11 gene, including the promoter, 5’UTR region and the first exon, the breaking point being in intron 1. It was performed exome analysis, to assess the genes possibly associated with osteoporosis, mainly osteogenesis imperfecta and, the genes associated with neurodevelopmental disorders, no pathogenic variants, or VUS
We presented a female patient with developmental delay, craniofacial dysmorphism, short stature, and very low bone mineral density with 16q24.3 duplication of 113 kb, involving three morbid OMIM genes, ANKRD11, RPL13, and PGN
Summary
The copy number variants (CNVs) involving 16q24.3 region are often associated with KBG syndrome (OMIM 148050), which is a rare genetic condition with autosomal dominant inheritance, firstly described by Hermann in 1975 [1]. The clinical picture is not always very evocative for this disorder, Low et al showing in a study on 32 patients with KBG syndrome that less than a half of these patients presented suggestive clinical features, the others having a more subtle clinical features, the diagnosis being established only after exome testing [8]. This duplication event involves the ANKRD11 gene, including the promoter, 5’UTR region and the first exon, the breaking point being in intron 1 It was performed exome analysis, to assess the genes possibly associated with osteoporosis, mainly osteogenesis imperfecta and, the genes associated with neurodevelopmental disorders, no pathogenic variants, or VUS (variants of uncertain significance) were detected
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