Ahdc1 is a potent regulator of obesity and energy metabolism.

AT-hook DNA-binding motif-containing protein 1 (AHDC1) is a causal gene of intellectual disability/developmental delay in humans. The biological role of AHDC1 is unclear. Recently, some clues from AHDC1 mutation carriers hinted that AHDC1 may participate in body-weight regulation. In this first metabolic phenotype study of Ahdc1 deficiency, we generated a Ahdc1-deficienct mouse line and found that Ahdc1 deficiency in both male and female mice led to adiposity from weaning and obesity characterized by reduced energy expenditure and respiratory quotient, with progressive development of hyperleptinemia, insulin resistance, abnormal glycolipid metabolism, and fatty liver. Our findings show that Ahdc1 is a novel key regulator of obesity and energy metabolism, which provides new insight into the physiological mechanisms of obesity.NEW & NOTEWORTHY In this first metabolic phenotype study of Ahdc1 deficiency, we generated a survivable Ahdc1-deficient mouse line. We found that Ahdc1 deficiency in both male and female mice resulted in adiposity from weaning and obesity characterized by reduced energy expenditure and respiratory quotient. Additionally, there was a progressive development of hyperleptinemia, insulin resistance, abnormal glycolipid metabolism, and fatty liver. These findings demonstrate that Ahdc1 is a novel key regulator of obesity and energy metabolism.

First reported cases with Xia-Gibbs syndrome from India harboring novel variants in AHDC1.

We report here two girls from different Indian families identified with novel variants in the AT Hook DNA Binding Motif Containing 1 gene (AHDC1) causing Xia-Gibbs syndrome. The diagnosis was made by clinical exome in both cases. Inconsistent dysmorphic features such as dolichocephaly in the first patient and brachycephaly in the second were observed. Prominent jaw and gelastic seizures were other features of patient 1. Thus, this syndrome, with developmental delay, poor expressive language and overlapping clinical phenotype requires the utility of next generation sequencing for diagnostic confirmation.

Phenotypic and protein localization heterogeneity associated with AHDC1 pathogenic protein-truncating alleles in Xia-Gibbs syndrome.

Xia-Gibbs syndrome (XGS) is a rare Mendelian disease typically caused by de novo stop-gain or frameshift mutations in the AT-hook DNA binding motif containing 1 (AHDC1) gene. Patients usually present in early infancy with hypotonia and developmental delay and later exhibit intellectual disability (ID). The overall presentation is variable, however, and the emerging clinical picture is still evolving. A detailed phenotypic analysis of 34 XGS individuals revealed five core phenotypes (delayed motor milestones, speech delay, low muscle tone, ID, and hypotonia) in more than 80% of individuals and an additional 12 features that occurred more variably. Seizures and scoliosis were more frequently associated with truncations that arise before the midpoint of the protein although the occurrence of most features could not be predicted by the mutation position. Transient expression of wild type and different patient truncated AHDC1 protein forms in human cell lines revealed abnormal patterns of nuclear localization including a diffuse distribution of a short truncated form and nucleolar aggregation in mid-protein truncated forms. Overall, both the occurrence of variable phenotypes and the different distribution of the expressed protein reflect the heterogeneity of this syndrome.

Clinical presentation and evolution of Xia-Gibbs syndrome due to p.Gly375ArgfsTer3 variant in a patient from DR Congo (Central Africa).

Xia-Gibbs syndrome (XGS) is a very rare genetic condition. The clinical spectrum is very broad and variable. The phenotype and evolution in a Congolese boy with XGS have been reported. At 6 years he had speech delay, drooling, marked hyperactivity, attention deficit, aggressive behavior, and intellectual disability. Dysmorphological evaluation revealed strabismus, mild unilateral ptosis, uplifted ear lobes, flat philtrum, thin upper lip vermillion, high arched palate, and flat feet. Patient-only whole exome sequencing identified a known pathogenic frameshift variant in the AHDC1 gene [NM_001029882.3(AHDC1):c.1122dupC;(p.Gly375ArgfsTer3)]. The clinical follow-up revealed the deterioration of his fine motor skills and significant cerebellar phenotype including tremor, pes cavus, and gait instability at the age of 12 years. This patient was compared with three previously reported patients with the same variant but did not identify a consistent pattern in the evolution of symptoms with age.

Atypical aplasia cutis in association with Xia Gibbs syndrome.

Xia Gibbs syndrome is a genetic disorder first defined in 2014 characterized by hypotonia, intellectual disability, global developmental delay, and dysmorphic facial features. While many additional features may be present, there are few reports of dermatologic findings. We report a case of atypical aplasia cutis in a female infant who was found to have Xia Gibbs syndrome. This case highlights consideration of cutaneous manifestations of Xia Gibbs syndrome which may aid in diagnosis.

The phenotypic spectrum of Xia-Gibbs syndrome.

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.

Xia-Gibbs syndrome (XGS) is a recently described neurodevelopmental disorder due to heterozygous loss-of-function AHDC1 mutations. XGS is characterized by global developmental delay, intellectual disability, hypotonia, and sleep abnormalities. Here we report the clinical phenotype of five of six individuals with XGS identified prospectively at the Children's Hospital of Philadelphia, a tertiary children's hospital in the USA. Although all five patients demonstrated common clinical features characterized by developmental delay and characteristic facial features, each of our patients showed unique clinical manifestations. Patient one had craniosynostosis; patient two had sensorineural hearing loss and bicuspid aortic valve; patient three had cutis aplasia; patient four had soft, loose skin; and patient five had a lipoma. Differential diagnoses considered for each patient were quite broad, and included craniosynostosis syndromes, connective tissue disorders, and mitochondrial disorders. Exome sequencing identified a heterozygous, de novo AHDC1 loss-of-function mutation in four of five patients; the remaining patient has a 357kb interstitial deletion of 1p36.11p35.3 including AHDC1. Although it remains unknown whether these unique clinical manifestations are rare symptoms of XGS, our findings indicate that the diagnosis of XGS should be considered even in individuals with additional non-neurological symptoms, as the clinical spectrum of XGS may involve such non-neurological manifestations. Adding to the growing literature on XGS, continued cohort studies are warranted in order to both characterize the clinical spectrum of XGS as well as determine standard of care for patients with this diagnosis.

Establishment of iPSC lines and zebrafish with loss-of-function AHDC1 variants: Models for Xia-Gibbs syndrome.

Xia-Gibbs syndrome (XGS) is a syndromic form of intellectual disability caused by heterozygous AHDC1 variants, but the pathophysiological mechanisms underlying this syndrome are still unclear. In this manuscript, we describe the development of two different functional models: three induced pluripotent stem cell (iPSC) lines with different loss-of-function (LoF) AHDC1 variants, derived by reprogramming peripheral blood mononuclear cells from XGS patients, and a zebrafish strain with a LoF variant in the ortholog gene (ahdc1) obtained through CRISPR/Cas9-mediated editing. The three iPSC lines showed expression of pluripotency factors (SOX2, SSEA-4, OCT3/4, and NANOG). To verify the capacity of iPSC to differentiate into the three germ layers, we obtained embryoid bodies (EBs), induced their differentiation, and confirmed the mRNA expression of ectodermal, mesodermal, and endodermal markers using the TaqMan hPSC Scorecard. The iPSC lines were also approved for the following quality tests: chromosomal microarray analysis (CMA), mycoplasma testing, and short tandem repeat (STR) DNA profiling. The zebrafish model has an insertion of four base pairs in the ahdc1 gene, is fertile, and breeding between heterozygous and wild-type (WT) animals generated offspring in a genotypic proportion in agreement with Mendelian law. The established iPSC and zebrafish lines were deposited on the hpscreg.eu and zfin.org platforms, respectively. These biological models are the first for XGS and will be used in future studies that investigate the pathophysiology of this syndrome, unraveling its underlying molecular mechanisms.

Genotype-phenotype spectrum and correlations in Xia-Gibbs syndrome: Report of five novel cases and literature review.

BACKGROUND: Xia-Gibbs syndrome (XGS) is a rare neurodevelopmental disorder caused by pathogenic variants in the AT-hook DNA-binding motif-containing 1 gene (AHDC1), encoding a protein with a crucial role in transcription and epigenetic regulation, axonogenesis, brain function, and neurodevelopment. AHDC1 variants possibly act through a dominant-negative mechanism and may interfere with DNA repair processes, leading to genome instability and impaired DNA translesion repair. Variants affecting residues closer to the N-terminal are thought to determine a milder phenotype with better cognitive performances. However, clean-cut genotype-phenotype correlations are still lacking. CASES: In this study, we investigated five subjects with XGS in whom exome sequencing led to the identification of five novel de novo pathogenic variants in AHDC1. All variants were extremely rare and predicted to cause a loss of protein function. The phenotype of the reported patients included developmental delay, hypotonia, and distinctive facial dysmorphisms. Additionally, uncommon clinical features were observed, including congenital hypothyroidism and peculiar skeletal abnormalities. CONCLUSIONS: In this study, we report uncommon XGS features associated with five novel truncating variants in AHDC, thus expanding the genotype and phenotypic spectrum of this complex condition. We also compared our cases to previously reported cases, discussing the current status of genotype-phenotype correlations in XGS.

Phenotypic heterogeneity and mosaicism in Xia-Gibbs syndrome: Five Danish patients with novel variants in AHDC1.

Xia-Gibbs syndrome (XGS) is a neurodevelopmental disorder characterized by intellectual disability, developmental delay, seizures, hypotonia, obstructive sleep apnoea and mild facial dysmorphism. Heterozygosity for loss-of-function variants in AHDC1, encoding the AT-hook DNA binding motif containing protein 1, were discovered in 2014 as the likely genetic cause of Xia-Gibbs syndrome. We present five patients with Xia-Gibbs syndrome caused by previously unreported variants in AHDC1. Two of the patients share a frameshift variant: c.2849del (p.(Pro950Argfs*192)) in AHDC1. Despite sharing this variant, the two patients show remarkable phenotypic differences underscoring the clinical heterogeneity of Xia-Gibbs syndrome. In addition, we present a case of Xia-Gibbs syndrome caused by mosaicism for an AHDC1 variant.

Microdeletion and microduplication of 1p36.11p35.3 involving AHDC1 contribute to neurodevelopmental disorder.

Xia-Gibbs syndrome is a rare genetic condition characterized by intellectual disability, growth retardation, delayed psychomotor development with absent or poor expressive language, distinctive facial features, hypotonia, laryngomalacia and obstructive sleep apnea. At present, Xia-Gibbs syndrome has been reported to be mainly caused by truncating mutations in AHDC1 gene located on chromosome 1p36.11. However, the evidence supporting AHDC1 deletion as a cause of this syndrome is still limited. Here we report an 8-year-old boy carrying a de novo 575 Kb microdeletion at 1p36.11 including AHDC1 gene. The boy is characterized by intellectual disability, developmental delay, short stature, expressive language delay, facial dysmorphism, obstructive sleep apnea and multiple congenital anomalies, which are mostly consistent with the characteristics of Xia-Gibbs syndrome. Therefore, we provide further supporting evidence that AHDC1 deletion causes Xia-Gibbs syndrome through a haploinsufficiency mechanism. Currently, clinical consequences of AHDC1 gene duplication has never been reported. Here, we identify a de novo 480 Kb duplication at 1p36.11p35.3 spanning the entire AHDC1 gene in a 2-year-8-month boy, who displays similar clinical features with that of Xia-Gibbs syndrome, in particular, expressive language delay, hypotonia, laryngomalacia and obstructive sleep apnea, as well as mirrored phenotypes such as overgrowth and advanced bone age. WES test excludes to the degree possible other known genetic causes. This case suggests that AHDC1 gene duplication may be clinical significance.

Extending the phenotype of Xia-Gibbs syndrome in a two-year-old patient with craniosynostosis with a novel de novo AHDC1 missense mutation.

Xia-Gibbs syndrome (Mental retardation, autosomal dominant 25; MRD25) [MIM 615829] is a rare autosomal dominant disease characterized by mental retardation, developmental delay, speech delay, structural brain anomalies, hypotonicity, protuberant eyes, visual problems, laryngomalacia and snoring. Since the first description in 2014, fewer than 50 patients with Xia-Gibbs syndrome have been noticed in the literature. We describe here 2 years 2 months old girl with developmental delay, brain anomalies, laryngomalacia and craniosynostosis. Whole-Exome Sequencing (WES) analyses in patient showed a heterozygous NM_001029882: c.4370 A>G; p. (Asp1457Gly) mutation in AHDC1. Craniosynostosis rarely observed in the patients described to date, and west syndrome-like EEG pattern, constipation and electrolyte imbalance observed for the first time were present in our patient. Further reports and in-vivo/in-vitro works will make possible knowing of the genetic and clinical background of this disease.

LINC01133 promotes the progression of cervical cancer by sponging miR-4784 to up-regulate AHDC1.

Cervical cancer, as the deadliest gynecological tumor with high risk of incidence, manifests aberrantly expressed lncRNAs in the malignant cellular processes. Long intergenic non-protein coding RNA 1133 (LINC01133) has been acknowledged to actively participate in aggressive tumor phenotypes. Our study focused on the identification of the function and corresponding mechanism of the novel molecule, LINC01133 in cervical cancer. LINC01133 expression profile was validated by digging The Cancer Genome Atlas (TCGA) database and qRT-PCR analysis. A considerably up-regulated expression of LINC01133 was unveiled. The results of CCK-8, trypan blue exclusion, EdU and transwell migration assays manifested the facilitating property of LINC01133 in cervical cancer. The epithelial-mesenchymal transition (EMT) was also exacerbated by LINCO1133. Apoptotic rate of cervical cancer cells was promoted after silencing LINCO1133. Mechanically, LINC01133 functioning as a ceRNA targeted miR-4784 to augment AHDC1 expression. Finally, LINCO1133/miR-4784 aggravated the malignant growth and aggressiveness and EMT of cervical cancer in an AHDC1-dependant way.

Two Chinese Xia-Gibbs syndrome patients with partial growth hormone deficiency.

BACKGROUND: Heterozygous mutations in the AT-hook DNA-binding motif containing one (AHDC1, OMIM * 615790) gene cause an autosomal dominant multisystem developmental disorder known as Xia-Gibbs syndrome (OMIM #615829). Xia-Gibbs syndrome typically presented with global developmental delay, hypotonia, obstructive sleep apnea, seizures, delayed myelination, micrognathia, and other mild dysmorphic features. METHODS: Description of the clinical materials of two Chinese boys who were diagnosed with Xia-Gibbs syndrome based on clinical presentations and next generation sequencing. Review of clinical features and AHDC1 mutations in previously reported Xia-Gibbs syndrome patients together with our two new patients. RESULTS: The Xia-Gibbs syndrome patients exhibited short stature, hypotonia, global developmental delay, speech delay, simian crease, and mild dysmorphic features. Next generation sequencing revealed de novo heterozygous variants in AHDC1 gene. In addition, laboratory test revealed partial growth hormone deficiency. Both patients underwent growth hormone replacement therapy for 24 and 9 months, respectively, and exhibited good response to the treatment. CONCLUSION: This is the first report of Xia-Gibbs syndrome patients to be treated with growth hormone. Review of previously reported Xia-Gibbs syndrome patient indicated that short stature is a frequent feature of this condition, but its underlying cause needs to be further investigated.

Whole-Exome Sequencing Identifies a de novo AHDC1 Mutation in a Colombian Patient with Xia-Gibbs Syndrome.

Xia-Gibbs syndrome is an autosomal dominant multisystem developmental disorder characterized by global developmental delay, hypotonia, obstructive sleep apnea, seizures, retrocerebellar cysts, delayed myelination, micrognathia, and mild dysmorphic features. Using whole-exome sequencing, we identified a de novo AHDC1 frameshift mutation c.2030_2030delG (p.G677Afs*52) in a Colombian patient, which was absent in both parents. Furthermore, we summarized the phenotypes of patients reported in the literature.

Clinical and genetic analysis of a Xia-Gibbs syndrome family / 中华神经科杂志

Objective To discuss clinical characteristics of a family with Xia-Gibbs syndrome, test and analyze the mutation of their pathogenic gene, and to explore the clinical and genetic characteristics of Xia-Gibbs syndrome. Methods A patient with unexplained developmental retardation was clinically examined and the medical history of his family was collected. Genetic detection was performed to analyze his genetic causes. Results The proband, who was two-year and 1-month old, displayed unusual facies, hypotonia and unexplained developmental retardation. Brain MRI showed leukodystrophy. Other members of his family had no similar medical history. And the proband was found to carry the de novo mutation of c.1073dupC in AHDC1 gene. Conclusion This is the first case with Xia-Gibbs syndrome caused by AHDC1 mutation in China, which has a great significance in studying the correlation between genotype and phenotype.