Genotype–phenotype spectrum and correlations in <scp>Xia‐Gibbs</scp> syndrome: Report of five novel cases and literature review

Romano, Ferruccio; Falco, Mariateresa; Cappuccio, Gerarda; Brunetti‐Pierri, Nicola; Lonardo, Fortunato; Torella, Annalaura; Digilio, Maria Cristina; Dentici, Maria Lisa; Alfieri, Paolo; Agolini, Emanuele; Novelli, Antonio; Garavelli, Livia; Accogli, Andrea; ,; Striano, Pasquale; Scarano, Gioacchino; Nigro, Vincenzo; Scala, Marcello; Capra, Valeria

doi:10.1002/bdr2.2058

Birth Defects Research

2022

DOI: 10.1002/bdr2.2058

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

Ferruccio Romano,

Mariateresa Falco,

Gerarda Cappuccio

et al.

Abstract: 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 Dr Ferruccio Romano and Mariateresa Falco have contributed equally. Dr Marcello Scala … Show more

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Cited by 3 publications

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Phenotypic subtypes of Xia-Gibbs syndrome: a latent class analysis

Jiang,

Zhang,

Zheng

et al. 2024

Eur J Hum Genet

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Xia-Gibbs syndrome (XGS) is a rare neurodevelopmental disorder with considerable clinical heterogeneity. To further characterize the syndrome’s heterogeneity, we applied latent class analysis (LCA) on reported cases to identify phenotypic subtypes. By searching PubMed, Embase, China National Knowledge Infrastructure and Wanfang databases from inception to February 2024, we enrolled 97 cases with nonsense, frameshift or missense variants in the AHDC1 gene. LCA was based on the following 6 phenotypes with moderate occurrence and low missingness: ataxia, seizure, autism, sleep apnea, short stature and scoliosis. After excluding cases with missing data on all LCA variables or with unmatched phenotype-genotype information, a total of 85 cases were selected for LCA. Models with 1–5 classes were compared based on Akaike Information Criterion, Bayesian Information Criterion, Sample-Size Adjusted BIC and entropy. We used multinomial logistic regression (MLR) analyses to investigate the phenotype-genotype association and potential predictors for class membership. LCA revealed 3 distinct classes labeled as Ataxia subtype (n = 11 [12.9%]), Sleep apnea & short stature subtype (n = 23 [27.1%]) and Neuropsychological subtype (n = 51 [60.0%]). The commonest Neuropsychological subtype was characterized by high estimated probabilities of seizure, ataxia and autism. By adjusting for sex, age and variant type, MLR showed no significant association between phenotypic subtype and variant position. Age and variant type were identified as predictors of class membership. The findings of this review offer novel insights for different presentations of XGS. It is possible to deliver targeted monitoring and treatment for each subtype in the early stage.

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Phenotypic subtypes of Xia-Gibbs syndrome: a latent class analysis

Jiang,

Zhang,

Zheng

et al. 2024

Eur J Hum Genet

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Ahdc1 is a potent regulator of obesity and energy metabolism

Li,

Shao,

Wang

et al. 2023

American Journal of Physiology-Endocrinology and Metabolism

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AT-hook DNA-binding domain 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 physiologic mechanisms of obesity.

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De novo AHDC1 Deletions Identified by Genome Sequencing in Two Individuals with Xia-Gibbs Syndrome

Bertrand,

Shah,

Pedersen

et al. 2024

Mol Syndromol

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Introduction: Xia-Gibbs syndrome (XGS) is a rare syndromic disorder characterized by developmental delay with intellectual disability, muscular hypotonia, brain anomalies, and nonspecific dysmorphic features. Different heterozygous variants in AHDC1 have been reported as causal for XGS, comprising mainly de novo stop-gain and frameshift events, but also missense variants, deletions, and a duplication of the locus. Case Presentation: We hereby report 2 patients with clinical features of XGS. In the first patient, a de novo interstitial deletion in 1p36.11p35.3 encompassing the entire coding region of AHDC1 was initially suspected by trio exome sequencing and subsequently confirmed by shallow genome sequencing. In the second patient, a de novo deletion comprising most of the 5′ untranslated region of AHDC1 was detected by genome sequencing. Conclusion: We identified the smallest deletion comprising AHDC1 reported so far by shallow genome sequencing as well as another small AHDC1 deletion by genome sequencing. These methods represent useful techniques for the identification and confirmation of small deletions and structural variants. Furthermore, our data provide additional evidence of AHDC1 haploinsufficiency as a disease mechanism in XGS. Clinically, foot deformity, skin and connective tissue abnormalities observed in one of the patients are consistent with other reported cases of XGS. These findings suggest that these manifestations could be considered as more prevalent characteristics, underscoring the importance of in-depth phenotyping.

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

Cited by 3 publications

References 28 publications

Phenotypic subtypes of Xia-Gibbs syndrome: a latent class analysis

Phenotypic subtypes of Xia-Gibbs syndrome: a latent class analysis

Ahdc1 is a potent regulator of obesity and energy metabolism

De novo AHDC1 Deletions Identified by Genome Sequencing in Two Individuals with Xia-Gibbs Syndrome

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