Osteopathia striata congenita with cranial sclerosis and intellectual disability due to contiguous gene deletions involving the WTX locus

Abstract

Osteopathia striata congenita with cranial sclerosis (OSCS) is a skeletal dysplasia caused by germline deletions of or truncating point mutations in the X-linked gene WTX (FAM123B, AMER1). Females present with longitudinal striations of sclerotic bone along the long axis of long bones and cranial sclerosis, with a high prevalence of cleft palate and hearing loss. Intellectual disability or neurodevelopmental delay is not observed in females with point mutations in WTX leading to OSCS. One female has been described with a deletion spanning multiple neighbouring genes suggesting that deletion of some neighbouring loci may result in abnormal neurodevelopment. In this cohort of 13 females with OSCS resulting from deletions of WTX, a relationship is observed where deletion of ARHGEF9 and/or MTMR8 in conjunction with WTX results in an additional neurodevelopmental phenotype whereas deletion of ASB12 along with WTX is associated with a good neurodevelopmental prognosis.

Wieacker–Wolff syndrome with associated cleft palate in a female case

“…In addition, a case report of a female with a contiguous gene deletion, which included the ZC4H2 and WTX gene was reviewed (Holman et al, ). This individual's genetic variations are associated with Osteopathia striata congenital with cranial sclerosis (OSCS).…”

“…OSC's common presentation includes longitudinal striations of sclerotic bone along long axis of long bones, cranial sclerosis and high prevalence of cleft palate, and hearing loss. Given the prior lack of association of cleft palate with ZC4H2 mutation, the authors postulated that her cleft palate was likely related to the known association with WTX gene and not ZC4H2 deletion (Holman et al, ). However, this increases the support of a possible association between a ZC4H2 mutation and cleft palate.…”

Osteopathia striata with cranial sclerosis and developmental delay in a male with a mosaic deletion in chromosome region Xq11.2

“…Interestingly, it has been recently suggested that the deletion of ARHGEF9 might contribute to the intellectual disabilities or the developmental delay seen in females with OSCS harboring a deletion of WTX and neighboring genes [Holman et al, 2012]. Unlike most cases with ARHGEF9 mutations, our patient does not have seizures [Harvey et al, 2004;Marco et al, 2008;Kalscheuer et al, 2009;Lesca et al, 2011;Shimojima et al, 2011;Holman et al, 2012]. This might be due to the normal expression of this gene in a significant proportion of his cells.…”

“…The phenotype of males with haploinsufficiency for this gene supports its role in cognitive development [Jedlicka et al, 2009;Papadopoulos et al, 2007;Lesca et al, 2011;Shimojima et al, 2011]. Interestingly, it has been recently suggested that the deletion of ARHGEF9 might contribute to the intellectual disabilities or the developmental delay seen in females with OSCS harboring a deletion of WTX and neighboring genes [Holman et al, 2012]. Unlike most cases with ARHGEF9 mutations, our patient does not have seizures [Harvey et al, 2004;Marco et al, 2008;Kalscheuer et al, 2009;Lesca et al, 2011;Shimojima et al, 2011;Holman et al, 2012].…”

“…Even if developmental delay and intellectual disability have been previously reported in males with WTX mutations resulting in mild OSCS , in our patient, we can not exclude the contribution of other genes located within the deleted region or disruption of regulatory sequences of neighboring genes. Notably, the ARHGEF9 gene maps within the deleted region in our patient and mutations of this gene have been associated with intellectual disabilities and seizures [Harvey et al, 2004;Marco et al, 2008; Kalscheuer et al, 2009;Lesca et al, 2011;Shimojima et al, 2011;Holman et al, 2012]. Previous studies have shown the pivotal role of ARHGEF9 in the formation of postsynaptic glycine and g-aminobutyric acid receptor clusters.…”