Abstract
Xia-Gibbs syndrome (XGS) is a very rare genetic condition. The clinical spectrum is very broad and variable.
We report the phenotype and evolution in a Congolese boy with XGS. 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. We compared this patient to three previously reported patients with the same variant but did not identify a consistent pattern in the evolution of symptoms with age.
Keywords: Xia-Gibbs syndrome, AHDC1, corpus callosum, tremor, Face2Gene
Introduction
Xia-Gibbs syndrome (XGS: OMIM # 615829) is a very rare genetic condition reported for the first time in 2014 (Xia et al., 2014). Manifestations include developmental delay and intellectual disability (DD/ID), behavior problems, hypotonia at birth, and brain anomalies (Cheng et al., 2019; Diaz-Ordonez et al., 2019; Gumus, 2020; Jiang et al., 2018; Wang et al., 2020). Speech is delayed, limited or absent. Genetic variants in the AT-hook DNA binding motif containing 1 gene (AHDC1) were identified as the cause of XGS (Yang et al., 2015), most patients having de novo variants.
The clinical spectrum of XGS is very broad with important interindividual clinical variability in terms of types or severity of manifestations, with no established genotype-phenotype correlation (Jiang et al., 2018; Ritter et al., 2018). The allelic heterogeneity, the limited number of patients with the same variant, and the age variations between patients have not facilitated clinical studies. The identification of additional patients with known variants and identification of ethnically diverse patients is a powerful strategy to improve the characterization of rare diseases across ethnicities, gain insights into the normal function of a gene and understand its disease mechanism. The recently developed Xia-Gibbs registry (Jiang et al., 2018) is a good tool to capture this diversity.
To date, approximately 100 patients have been reported from Latin America, Europe and Asia. No patient from Africa has been reported thus far. In this report, the clinical presentation and evolution of XGS is described in the first identified African XGS patient. We also compare this patient to previously reported patients with the same variant.
CLINICAL REPORT
We report a boy from the Democratic Republic of Congo, Central Africa. He is the second of 4 children, born to unrelated Congolese parents in their thirties at the time of birth. He was first seen when he was 6.15-year-old. The three other siblings are healthy girls. The father experienced a sudden death a few months after being diagnosed with a heart problem for which no additional clinical details were available. Pregnancy and delivery were uneventful. The proband was born at term weighing 3kg (−0.92 SD), and other birth measurements were not available. Gross motor development was delayed: he sat at 12 months and walked independently after the age of 24 months. No fine motor delay was reported or noticed. He did not develop intelligible speech and had drooling. His behavior was marked by hyperactivity, attention deficit, impulsivity, aggressive behavior with self-injuries and limited interactions with strangers. He has severe intellectual disability and attended a special school for children with intellectual disability. At the age of 5 years he underwent a valvuloplasty for mitral valve insufficiency.
Growth parameters at 6.15 years were within normal limits including head circumference of 52 cm (+0.2 SD), height of 111 cm (−1.05 SD) and weight of 19.8 kg (−0.45 SD). Dysmorphological evaluation revealed strabismus, mild unilateral ptosis, ears with distinctive folding of helix and uplifted lobes, flat philtrum, thin upper lip vermillion, high arched palate, flat feet (Figure 1a). Proposed clinical differential diagnoses included Noonan and Mowat-Wilson syndromes. Facial photograph was evaluated with Face2Gene (FDNA, Inc., Boston, MA), which also returned Noonan syndrome as the top match for the patient.
Figure 1.
Phenotype in our patient.
Legend: Panel A shows dysmorphism at 6 years of age including ears with distinctive folding of helix and uplifted lobes (A1-A4); strabismus, mild unilateral ptosis, bulbous nose tip, flat philtrum, thin upper lip vermillion (A2-A3); flat feet (A5); mild clinodactyly of the 5th finger on right hand and otherwise non-peculiar hands and fingers (A6); high arched palate (A7). Panel B shows that our patient, at the age of 12, has retained the same facial dysmorphism (B1-B2) and hand morphology (B5) but show thinning of the corpus callosum predominant posteriorly and enlarged posterior fossa (B3) and pes cavus (B4).
At the age of 8 years a blood sample was obtained and DNA extraction was performed at the Center for Human Genetics of the University of Kinshasa (DR Congo) and patient-only Exome Sequencing (ES) testing at the Baylor College of Medicine (Texas, USA) through the Baylor Hopkins Center for Mendelian Genomics (BHCMG). Library preparation, sequencing platform and bioinformatic analysis were as previously described (Lumaka et al., 2018).
The first analysis of the ES data did not return a plausible candidate variant for the clinical differential diagnosis. The ES were re-analyzed 4 years later, when the patient was 12.32-year-old, and identified a relevant and recently published pathogenic variant in the AHDC1 (Yang et al., 2015), the gene responsible for XGS.
Clinical interpretation using Moon® platform (http://www.diploid.com/moon) identified a known pathogenic heterozygous duplication of one nucleotide in the AHDC1 gene NM_001029882.3(AHDC1):c.1122dupC;(p.Gly375ArgfsTer3). The variant was validated by Sanger sequencing and was shown to be absent from the mother (supplemental figure S1). Paternal sample is unavailable to assess for de novo status of the variant.
The patient was re-evaluated after ES diagnosis was reached. He still had no speech, retained aggressive behavior with self-injuries and resistance to change. Despite valvuloplasty, he had some mitral valve insufficiency. Of note, hypotonia and drooling were more marked. Fine motor regression was also noticed. He developed tremor, unstable gait and ataxic walk (supplemental video S2) that were not present at the age of 6.15 years. The growth parameters remained within normal limits although there was a relative increase in head circumference and a decrease in weight: head circumference 56 cm (+1.19 SD), height 147 cm (−0.55 SD) and weight 34 kg (−1.18 SD). The patient presented with the same dysmorphic features except for the ptosis that had resolved. Conversely, his feet demonstrated pes cavus deformity (Figure 1b).
MRI showed thinning of the corpus callosum predominant posteriorly and enlarged posterior fossa (Figure 1b3). These clinical features were determined to be consistent with a diagnosis of XGS in this patient.
DISCUSSION
We present the phenotypic description and the phenotypic evolution after 6 years in the first Sub-Saharan African patient with XGS. Although this boy presented with severe developmental delay, he did not present with growth retardation as observed in other XGS patients. As with previously reported XGS patients, the XGS diagnosis was not initially suspected clinically. A XGS mask was previously constructed in Face2Gene to facilitate recognition of XGS facial gestalt (Jiang et al., 2018). In the current patient, Face2Gene did not list XGS among the top 30 suggested matches for facial photographs at 6 years nor at 12 year. In two Caucasian XGS patients, the diagnosis of XGS was returned by Face2Gene as first in one of them and as second (after Noonan syndrome) in the second patient. This suggests a possible influence of African phenotypic background on facial recognition. This underscores the need for increased diversity within the databases often used as a training set for artificial intelligence tools.
The clinical variability of XGS has been ascribed to allelic heterogeneity and to the age differences between reported patients. The variant identified in our patient was previously reported in one child in the US and one girl and her relative (fetus) from China (He et al., 2020; Yang et al., 2015). The clinical follow-up of the present patient showed a deterioration of his motor skills with regards to the fine motor and of cerebellar phenotype including tremor, pes cavus and gait instability. However, when comparing our patient to previously reported patients with this same variant (table 1), we did not observe a clear path to worsening. The cerebral phenotype that appeared later in our patient was already observed at the age of 4 years in 2 other patients with the same variant. Longitudinal studies of large series can illuminate the evolution of the phenotype over age.
Table 1.
Phenotype in p.Gly375ArgfsTer3 patients
| Publication | Patient | Age (years) | Inheritance | Gender | DD | cognitive delay | Age at walking | current speech | hypotonia | Dysmorphism | Brain abnormality | Other neurobehavior problem |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PMID: 27148574 | #4 | 4 | de novo | F | + | + | 20 mo | Single words | + | − | Small Corpus Callosum, loss of posterior ventricular white matter | Wide based gait, nystagmus |
| PMID: 31812316 | #1 | 4 | maternal germline mosaicism | F | + | NA | NA | Absent | + | + | corpus callosum thinning | ataxic gait with poor balance, asymmetric bilateral sensorineural hearing loss |
| #2 | Fetus | maternal germline mosaicism | M | NA | NA | NA | NA | NA | NA | fetal hypoplasia of corpus callosum | ||
| Current Report* | #1 | 6 | NA | M | + | + | 24 mo | Absent | + | strabismus, mild unilateral ptosis, peculiar folding of helix and uplifted lobes, flat philtrum, thin upper lip vermillion, high arched palate, flat feats | NA | ADHD, aggressive behavior, self-injuries, autistic like behavior |
| Current report* | #1 | 12 | NA | + | + | Absent | + | no ptosis but presence of pes cavus | Small corpus callosum with increased thinning, posterior Posterior cyst | occurrence of tremor, unstable gait and ataxic walk |
The same patient is presented at two different ages
This patient also demonstrates the value of reanalyzing extant genomic data in light of increasing evidence in the literature and databases. More importantly, this report offers the first look at a XGS patient from Sub-Saharan Africa.
Supplementary Material
Sanger sequencing chromatogram.
Legend: from the top to the bottom are the patient, his mother and 2 controls from the same population. Note the heterozygous frameshift on the patient’s chromatogram.
Video of patient at 11 years showing tremor and gait instability
ACKNOWLEDGEMENTS
The authors are grateful to Prof Richard Gibbs for his advice and revision of this manuscript.
Funding information
Baylor-Hopkins Center for Mendelian Genomics, BHCMG: National Human Genome Research Institute/National Heart Lung and Blood Institute; Grant/Award Number UM1 HG006542; KU LEUVEN Flanders Research Fund (FWO), Grant/Award Number: K210115 and V405213N Liège University, Grant from the Région Wallonne: RWAL1710180 (WALGEMED)
Footnotes
CONFLICT OF INTEREST STATEMENT
J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from molecular genetic testing offered in the Baylor-Genetics Laboratories.
The other authors declare no conflict of interest.
DATA AVAILABILITY STATEMENT
The data that support the findings including photographs are submitted to the Xia-Gibbs registry. Those data are also available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Sanger sequencing chromatogram.
Legend: from the top to the bottom are the patient, his mother and 2 controls from the same population. Note the heterozygous frameshift on the patient’s chromatogram.
Video of patient at 11 years showing tremor and gait instability
Data Availability Statement
The data that support the findings including photographs are submitted to the Xia-Gibbs registry. Those data are also available from the corresponding author upon reasonable request.