Neurodevelopmental Disorder, Obesity, Pancytopenia, Diabetes Mellitus, Cirrhosis, and Renal Failure in ACBD6 -Associated Syndrome

Abstract

ObjectivesNeurodevelopmental disorders (NDDs) are a group of conditions that are clinically and etiologically heterogeneous. Biallelic variants inACBD6were previously reported in 7 patients with NDDs. Unfortunately, their clinical information remains very limited with descriptions of only their neurologic and craniofacial features. The purpose of this report is to expand the clinical phenotype of theACBD6-associated NDDs.MethodsWe identified 2 Thai siblings with NDDs. Clinical and radiologic features of the proband were described. The affected siblings and parents underwent whole-exome sequencing and PCR-Sanger sequencing.ResultsClinical manifestations that have never been previously reported include morbid obesity, pancytopenia with severe infections, diabetes mellitus, cirrhosis, and renal failure, leading to deaths in their early 30s. Molecular studies identified a novel homozygous 1 base-pair duplication (c.360dup; p.Leu121Thrfs*27) in theACBD6gene.DiscussionThis study reported 1 novel single base-pair duplication, expanding the mutational spectrum, and described the clinical features establishing the entity ofACBD6-associated NDDs.

Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders

“…Three variants, including p.(Gly22fs), p.(Leu121ThrfsTer27) and a 30 kb deletion in the C-terminus, have been reported previously. 6 , 7 , 10 Recurrent variants are labelled with family codes. ( C ) Splicing schematic for the c.574-2A>G ( top ) variant in ACBD6 showing cryptic acceptor splice site activation in exon 6.…”

“…Follow-up details were obtained in the family reported by Yeetong et al . 10 For a comprehensive phenotypic characterization of the affected individuals, we obtained clinical details, including neurological examination, via a universally-adopted proforma ( Supplementary Table 1 ). Where possible, video recordings and facial photographs of the affected individuals along with their brain MRIs were made available for review by a movement disorders specialist (K.B.…”

“… 4-7 ACBD6 has been suggested as a candidate gene for intellectual disability (ID) in two large-cohort gene discovery studies reporting limited phenotypic data 8 , 9 and in a case report describing two siblings with neurodevelopmental disorder, obesity, pancytopenia, diabetes mellitus, cirrhosis and renal failure but with a limited neurological phenotype. 10 …”