Congenital immobility and stiffness related to biallelic ATAD1 variants

Abstract

Objective: To delineate the phenotype associated with biallelic ATAD1 variants.

Methods: We describe 2 new patients with ATAD1-related disorder diagnosed by whole-exome sequencing and compare their phenotype to 6 previous patients.

Results: Patients 1 and 2 had a similar distinctive phenotype comprising congenital stiffness of limbs, absent spontaneous movements, weak sucking, and hypoventilation. Both had absent brainstem evoked auditory responses (BEARs). Patient 1 carried the homozygous p.(His357Argfs*15) variant in ATAD1. In the light of the finding in patient 1, a second reading of exome data for patient 2 revealed the novel homozygous p.(Gly128Val) variant.

Conclusions: Analysis of the phenotypes of these 2 patients and of the 6 previous cases showed that biallelic ATAD1 mutations are responsible for a unique congenital encephalopathy likely comprising absent BEAR, different from hyperekplexia and other conditions with neonatal hypertonia.

Figure. Pedigrees, electrophoregrams, and BEAR

(A) Pedigree (A.a) and electrophoregrams (A.b) showing the homozygous p.(His357Argfs*15) variant in the proband and the heterozygous state of his parents. BEARs were absent with stimulation up to 90 and 105 dB (A.c). (B) Pedigree (B.a) of patient 2 and electrophoregrams (B.b) showing the homozygous p.(Gly128Val) variant in the proband and the heterozygous state of his parents. BEARs were also absent in patient 2 with stimulation up to 90 and 105 dB (B.c). BEAR = brainstem evoked auditory response.