• AHDC1
• DNA methylation
• Gibbin
• Xia-Gibbs syndrome
• chromatin
• gene transcription

• AHDC1
• Deletion
• Foot deformity
• Shallow genome sequencing
• Xia-Gibbs syndrome

• R01 HG009141 NHGRI NIH HHS
• U01 HG011755 NHGRI NIH HHS
• UM1 HG008900 NHGRI NIH HHS

• Conjunctival melanosis
• Craniosynostosis
• Intellectual disability
• Pes cavus
• Xia-Gibbs syndrome

• Ahdc1
• energy metabolism
• obesity

• Humans
• Male
• Animals
• Female
• Mice
• Insulin Resistance/genetics
• Obesity/genetics
• Obesity/metabolism
• Adiposity/genetics
• Fatty Liver
• Energy Metabolism/genetics
• Glycolipids
• DNA-Binding Proteins/genetics

• contiguous gene deletion syndromes
• gene expression
• posttranscriptional gene regulation
• rare Mendelian disease traits

• Humans
• Abnormalities, Multiple/genetics
• DNA-Binding Proteins/genetics
• Endoribonucleases
• Intellectual Disability/genetics
• Musculoskeletal Abnormalities
• Neurodevelopmental Disorders/genetics
• Phosphoprotein Phosphatases
• Qa-SNARE Proteins
• RNA-Binding Proteins
• Sphingomyelin Phosphodiesterase

• T15 LM007093 NLM NIH HHS

Xia–Gibbs syndrome (XGS, OMIM: 615829), caused by mutations within the AT-Hook DNA-binding motif-containing protein 1 (AHDC1) gene (OMIM: 615790), located on the short arm of chromosome 1 within the cytogenetic band 1p36.11, contains five noncoding 5 exons, a single 4.9-kb coding exon, and a noncoding 3 exon.

In this case report, we diagnosed and treated a 6-mo-old girl with XGS. The primary clinical symptoms included global developmental delay, hypotonia, and mild dysmorphic features. Using high-throughput whole-exosome sequencing to sequence the patient and her parents, and the results showed a novel frameshift mutation of c.1155dupG (p.Arg386Alafs*3) in the AHDC1 gene. The paternal gene was wild type.

This report extends the mutation spectrum of the AHDC1 gene to provide the diagnostic basis for genetic counseling in families with XGS.

• Xia–Gibbs syndrome
• AT-Hook DNA-binding motif-containing protein 1
• Children
• Global developmental delay
• Case report

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.

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.

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.

• AHDC1
• DNA repair
• Xia-Gibbs syndrome
• genotype-phenotype correlations
• loss-of-function variant
• neurodevelopmental syndrome

Background: Xia–Gibbs syndrome (XGS) is a rare disorder caused by de novo mutations in the AT-Hook DNA binding motif Containing 1 (AHDC1) gene, which is characterised by a wide spectrum of clinical manifestations, including global developmental delay, intellectual disability, structural abnormalities of the brain, global hypotonia, feeding problems, sleep difficulties and apnoea, facial dysmorphisms, and short stature. Methods: Here, we report on a girl patient who shows a peculiar cognitive and behavioural profile including high-functioning autism spectrum disorder (ASD) without intellectual disability and provide information on her developmental trajectory with the aim of expanding knowledge of the XGS clinical spectrum. On the basis of the current clinical case and the literature review, we also attempt to deepen understanding of behavioural and psychiatric manifestations associated with XGS. Results: In addition to the patient we described, a considerable rate of individuals with XGS display autistic symptoms or have been diagnosed with an autistic spectrum disorder. Moreover, the analysis of the few psychopathological profiles of patients with XGS described in the literature shows a frequent presence of aggressive and self-injurious behaviours that could be either an expression of autistic functioning or an additional symptom of the ASD evolution. A careful investigation of the abovementioned symptoms is therefore required, since they could represent a “red flag” for ASD.

• Xia–Gibbs syndrome
• autism spectrum disorder
• genetic autism

• growth hormone replacement therapy
• neurodevelopmental treatment
• paediatric neurology
• physiotherapy
• rare genetic disorder
• rehabilitation
• whole-exome sequencing
• xia-gibbs syndrome

• Exome sequencing
• Intellectual disability
• Neurodevelopmental disorders
• Novel mutation
• Sanger sequencing

• intellectual disability, severe
• severe global developmental delay

• Abnormalities, Multiple/diagnosis
• Abnormalities, Multiple/genetics
• Abnormalities, Multiple/pathology
• Heterozygote
• Humans
• Intellectual Disability/diagnosis
• Intellectual Disability/genetics
• Intellectual Disability/pathology
• Male
• Middle Aged
• Exome Sequencing

• U54 HG006542 NHGRI NIH HHS
• UM1 HG006542 NHGRI NIH HHS

• Frameshift mutations
• Whole exome sequencing
• Developmental disabilities

• AHDC1
• de novo mutation
• intellectual disability

• Autism Spectrum Disorder/etiology
• Child
• Cognition/physiology
• Corpus Callosum/diagnostic imaging
• Corpus Callosum/pathology
• DNA-Binding Proteins/genetics
• Developmental Disabilities/etiology
• Face/abnormalities
• Female
• Humans
• Male
• Mutation
• Pedigree
• Phenotype
• Registries
• Seizures/etiology
• Syndrome
• Young Adult

• U54 HG006542 NHGRI NIH HHS
• UM1 HG006542 NHGRI NIH HHS
• K08 HG008986 NHGRI NIH HHS
• UM1 HG008898 NHGRI NIH HHS
• R01 HG011795 NHGRI NIH HHS
• MC_UU_00007/15 Medical Research Council
• MC_UU_12008/1 Medical Research Council