RESUMEN
WAC-related intellectual disability (ID) is a rare genetic condition characterized by a spectrum of neurodevelopmental disorders of varying severity, including global developmental delay (GDD), ID, and autism spectrum disorder. Here, we describe five affected individuals, age range 9-20 years, and provide proof of pathogenicity of a novel splicing variant. All individuals presented with GDD, some degree of ID, and variable dysmorphism. Except for feeding difficulties, all patients were healthy without major congenital malformations or medical comorbidities. All individuals were heterozygous for de novo, previously unreported, loss of function variants in WAC. Three unrelated patients from different ethnic backgrounds shared the intronic variant c.381+4_381+7delAGTA, which was predicted to alter splicing and was initially classified as a variant of uncertain significance. Reverse transcription-polymerase chain reaction analysis from one patient's cells confirmed aberrant splicing of the WAC transcript resulting in premature termination and a truncated protein p.(Gly92Alafs*2). These functional studies and the identification of several nonrelated individuals provide sufficient evidence to classify this variant as pathogenic. The clinical description of these five individuals and the three novel variants expand the genotypic and phenotypic spectrum of this ultrarare disease.
Asunto(s)
Trastorno del Espectro Autista , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Proteínas Adaptadoras Transductoras de Señales/genética , Adolescente , Adulto , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/genética , Niño , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Mutación , Adulto JovenRESUMEN
We report three unrelated probands, two male and one female, diagnosed with Aicardi-Goutières syndrome (AGS) after screening positive on California newborn screening (CA NBS) for X-linked adrenoleukodystrophy (X-ALD) due to elevated C26:0 lysophosphatidylcholine (C26:0-LPC). Follow-up evaluation was notable for elevated C26:0, C26:1, and C26:0/C22:0 ratio, and normal red blood cell plasmalogens levels in all three probands. Diagnoses were confirmed by molecular sequencing prior to 12 months of age after clinical evaluation was inconsistent with X-ALD or suggestive of AGS. For at least one proband, the early diagnosis of AGS enabled candidacy for enrollment into a therapeutic clinical trial. This report demonstrates the importance of including AGS on the differential diagnosis for individuals who screen positive for X-ALD, particularly infants with abnormal neurological features, as this age of onset would be highly unusual for X-ALD. While AGS is not included on the Recommended Universal Screening Panel, affected individuals can be identified early through state NBS programs so long as providers are aware of a broader differential that includes AGS. This report is timely, as state NBS algorithms for X-ALD are actively being established, implemented, and refined.