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

Abstract

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.

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

“…In a recent work by Khayat et al, truncating mutations closer to the N‐terminus were more likely associated with seizures or scoliosis (Khayat et al, 2021). However, phenotypic heterogeneity is not uncommon in individuals harboring the same variant, suggesting that clear‐cut genotype–phenotype correlations are difficult to establish (Jiang et al, 2018; Mubungu et al, 2020). In fact, two unrelated children carrying the c.2849del (p.Pro950Argfs*192) variant have been recently reported to show significantly different phenotypes (Faergeman et al, 2021).…”

Increasing African genomic data generation and sharing to resolve rare and undiagnosed diseases in Africa: a call-to-action by the H3Africa rare diseases working group

“…gov/ clinv ar/), against a good population database illustrated enrichment of ClinVar with a significant proportion of wrongly ascertained variants [27]. Also, reanalysis of NGS data after databases have been populated helped in both identifying previously discarded plausible variants and down-classifying previously misclassified variants [28][29][30][31]. Such misclassification was found to be higher in individuals of African ancestry [32].…”

“…In addition, there is an important contribution of NGS tests free-of-charge to African rare diseases patients from international research collaborations and philanthropic initiatives such as the Centers for Mendelian Genomics (CMG) [12] and the iHope foundation. All these efforts have allowed ending diagnostic odyssey in many African patients and adjusting care when possible as well as identifying new disease genes [13][14][15][16][17][18].…”

“…The first consequence of the underrepresentation of African samples from commonly used databases is the higher level of difficulty to reach a molecular diagnosis in African individuals. The data disparity ultimately results in health disparity [17]. There is a risk that NGS will be perceived as deeply flawed and thus of limited clinical utility for some populations, which would work against all of the efforts to make this technology more accessible on the African continent.…”

Phenotypic and protein localization heterogeneity associated with AHDC1 pathogenic protein‐truncating alleles in Xia–Gibbs syndrome

“…and overlaps with other disorders, making it challenging to diagnose based on clinical presentation alone. All reported diagnoses have so far been established by DNA sequence-based approaches (Cardosodos-Santos et al, 2020;Cheng et al, 2019;Díaz-Ordoñez et al, 2019;García-Acero & Acosta, 2017;Gumus, 2020;He et al, 2020;Jiang et al, 2018;Mubungu et al, 2020;Murdock et al, 2019;Ritter et al, 2018;Xia et al, 2014;H. Yang et al, 2015;S.…”