De novo dominant variants affecting the motor domain of KIF1A are a cause of PEHO syndrome

Abstract

PEHO syndrome (OMIM no. 260565) is characterized by myoclonic jerking and infantile spasms, profound psychomotor retardation with the absence of motor milestones and speech, absence or early loss of visual fixation with atrophy of optic discs by 2 years of age and progressive brain atrophy on neuroimaging. We describe the results of a genomic study of a girl with PEHO syndrome and review the literature on cases with a disease-causing variant in the same gene. Exome sequencing of the index and unaffected parents followed by Sanger confirmation identified nine candidate genes harboring nonsynonymous rare variants identified by trio whole-exome sequencing. The de novo variant, a missense variant (c.296C4T, p.(T99M)), affecting the motor domain of KIF1A was considered the pathogenic mutation. The literature review revealed 24 cases with disease-causing variants in the motor domain of KIF1A, of which three met all the criteria for PEHO syndrome and an additional patient with incomplete clinical data met four of the five criteria. If the criteria were modified to include cases with any convulsive disorder and less profound intellectual disability, a total of six patients met all five of the criteria, three patients met four of the criteria and six met three of the criteria. Our results indicate that the molecular basis for PEHO syndrome, in at least a subset of patients, is a dominant KIF1A variant affecting the motor domain of the protein. Variable expressivity is seen with recurrent variants causing the full phenotype of PEHO syndrome in some patients and in other patients, a partial or milder PEHO phenotype.

Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A ( KIF1A )

“…Case 4 with p.(Thr99Met) variant in KIF1A shared common clinical features with the previously reported patients with this variant such as abnormal muscle tone, seizures, intellectual disability, gait abnormalities, optic nerve abnormalities (Hamdan et al, 2011; Langlois et al, 2016; Lee et al, 2015). In addition, she exhibited features described in RTT such as a period of regression followed by stabilization as well as characteristic stereotypic hand movements.…”

Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia

“…However, recently several independent reports have identified variants in this gene in autosomal dominant forms of HSP (MRD9, MIM 614255). Twenty-two probands with de novo variants are reported with complicated form of HSP including a recent case of PEHO syndrome (MIM 260565) [43]. However, a pure HSP phenotype has previously been presented in one family, with a dominantly segregating variant, p.(Ser69Leu) [44].…”

PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment

“…Since the original clinical description of this condition in 1991, a number of different genes and modes of inheritance have been associated with clinical presentations said to be consistent with PEHO, or thought to be PEHO-like in nature, including de novo dominant variants in CDKL5 and KIF1A and biallelic mutations in CCDC8A (Gawlinski et al , 2016; Langlois et al , 2016; Nahorski et al , 2016) . The phenotype in the Italian family, as well as consistent overlapping clinical aspects present in the other families described here, provides cause to consider that PRUNE1 should now also be added to the list of genes in which mutations may present in children with epileptic encephalopathy and PEHO-like features.…”