The phenotypic spectrum of Xia‐Gibbs syndrome

Abstract

Xia-Gibbs syndrome (XGS: OMIM # 615829) results from de novo truncating mutations within the AT-Hook DNA Binding Motif Containing 1 gene (AHDC1). To further define the phenotypic and molecular spectrum of this disorder, we established an XGS Registry and recruited patients from a worldwide pool of approximately 60 probands. Additional de novo truncating mutations were observed among 25 individuals, extending both the known number of mutation sites and the range of positions within the coding region that were sensitive to alteration. Detailed phenotypic examination of 20 of these patients via clinical records review and data collection from additional surveys showed a wider age range than previously described. Data from developmental milestones showed evidence for delayed speech and that males were more severely affected. Neuroimaging from six available patients showed an associated thinning of the corpus callosum and posterior fossa cysts. An increased risk of both scoliosis and seizures relative to the population burden was also observed. Data from a modified autism screening tool revealed that XGS shares significant overlap with autism spectrum disorders. These details of the phenotypic heterogeneity of XGS implicate specific genotype/phenotype correlations and suggest potential clinical management guidelines.

Variable Clinical Manifestations of Xia‐Gibbs syndrome: Findings of Consecutively Identified Cases at a Single Children's Hospital

“…ond or third decades nor other adult-onset manifestations of the condition Jiang et al, 2018. also reported several individuals over 18 years old with similar lack of neurologic decline in early adulthood.Patient 2 had hearing loss, bicuspid aortic valve, and aortic valve regurgitation.…”

Two Chinese Xia‐Gibbs syndrome patients with partial growth hormone deficiency

“…Here, we described two unrelated Chinese male patients who carried de novo frameshift mutations, c.2889_2892delTGCC (p.A964fs*177) and c.2373_2374delTG (p.Cys791Trpfs*57) in AHDC1 gene. The first mutation is novel and the second one is a recurrent pathogenic variant that had been reported in four Xia‐Gibbs patients (Jiang et al, ; Xia et al, ; Yang et al, ). The evaluation of Chinese patients with Xia‐Gibbs syndrome helped to expand both clinical and molecular spectra of this condition.…”

“…Both mutations were confirmed by Sanger sequencing and were absent in both parental samples. The variant in patient 1 is novel, the variant in patient 2 is a recurrent variant (Jiang et al, ; Xia et al, ; Yang et al, ). Both variants are classified as pathogenic flowing the ACMG/AMP sequence variant classification guideline.…”

“…Xia‐Gibbs syndrome is a recently described genetic disorder caused by heterozygous mutations in the AHDC1 gene (Bosch et al, ; García‐Acero & Acosta, ; Jiang et al, ; Xia et al, ; Yang et al, ) which encodes an AT‐hook DNA‐binding motif‐containing protein 1(Reeves & Nissen, ). So far there were been 27 patients reported with Xia‐Gibbs syndrome, most of them were Caucasians (Jiang et al, ). They were mainly diagnosed through the identification of de novo variants in AHDC1 gene by exome sequencing.…”

“…They were mainly diagnosed through the identification of de novo variants in AHDC1 gene by exome sequencing. Patients with Xia‐Gibbs syndrome were typically presented with global developmental delay, hypotonia, obstructive sleep apnea, seizures, delayed myelination, micrognathia, and other mild dysmorphic features (Bosch et al, ; García‐Acero & Acosta, ; Jiang et al, ; Xia et al, ; Yang et al, ). Yet the whole spectrum of the phenotype is not well established, especially among patients with other ethnicities.…”