Genotype-phenotype correlations and expansion of the molecular spectrum of AP4M1-related hereditary spastic paraplegia

Abstract

BackgroundAutosomal recessive hereditary spastic paraplegia (HSP) due to AP4M1 mutations is a very rare neurodevelopmental disorder reported for only a few patients.MethodsWe investigated a Greek HSP family using whole exome sequencing (WES).ResultsA novel AP4M1A frameshift insertion, and a very rare missense variant were identified in all three affected siblings in the compound heterozygous state (p.V174fs and p.C319R); the unaffected parents were carriers of only one variant. Patients were affected with a combination of: (a) febrile seizures with onset in the first year of life (followed by epileptic non-febrile seizures); (b) distinctive facial appearance (e.g., coarse features, bulbous nose and hypomimia); (c) developmental delay and intellectual disability; (d) early-onset spastic weakness of the lower limbs; and (e) cerebellar hypoplasia/atrophy on brain MRI.ConclusionsWe review genotype-phenotype correlations and discuss clinical overlaps between different AP4-related diseases. The AP4M1 belongs to a complex that mediates vesicle trafficking of glutamate receptors, being likely involved in brain development and neurotransmission.Electronic supplementary materialThe online version of this article (10.1186/s13023-017-0721-2) contains supplementary material, which is available to authorized users.

Whole exome sequencing in neurogenetic odysseys: An effective, cost- and time-saving diagnostic approach

“…Furthermore, we were able to expand the phenotypic spectrum of known genes and identify new pathogenic variants in other genes. Two cases were illustrative of common themes in medical genomics [ 17 , 18 ]. A non-sense mutation in GRIK2 caused a more complex phenotype than it was previously recognized for this gene.…”

Integrating structural and evolutionary data to interpret variation and pathogenicity in adapter protein complex 4

“…Sivley et al 34,35 developed a program called PathProx that evaluates the relative 3D proximity of a variant to known pathogenic and benign variants. To explore the spatial distribution of variants in AP‐4, we mapped onto the AP‐4 homology model four reported pathogenic variants (curated from the literature) 13–16,36 and six variants annotated as likely pathogenic in ClinVar (Table 3). 32 We also identified 699 likely benign variants in AP‐4 from gnomAD database (Figure 4).…”

“…The complex is expressed ubiquitously in cells, but AP‐4 seems especially important for neurological development 9–12 . Each of the four subunits can harbor mutations that cause hereditary spastic paraplegias (HSPs), 13–16 and current clinical research suggests patients have a specific subtype of HSP called AP‐4 deficiency syndrome 17 . Each AP‐4 gene ( AP4E1/AP4B1/AP4M1/AP4S1 ) is also classified as a spastic paraplegia gene ( SPG51/SPG47/SPG50/SPG52 , respectively).…”

Locus and allelic heterogeneity in five families with hereditary spastic paraplegia

“…Autosomal recessive HSP due to pathogenic variants in AP4M1 (Spastic paraplegia 50) is a rare neurodevelopmental disorder reported for only a few patients. Seven pathogenic AP4M1 mutations in seven families have been reported to date 15 . Copy number variants including the AP4M1 have also been implicated in developmental anomalies 16 .…”

“…The spectrum of clinical findings observed in the patients in the literature are of infantile hypotonia, intellectual disability, developmental delay, early-onset spastic paraplegia, variable white matter and cerebellar involvement on brain MRI 17–21 . A genotype-phenotype correlation has been proposed earlier as early onset and severe phenotype was often noted in individuals with truncating variants in comparison to missense variants in individuals with milder phenotype 15 . Proband in family 4 (P6) possessed a canonical splicing variant and manifested classical signs of AP-4 complex deficiency like seizures (precipitated by fever), distinctive facial appearance, hypotonia, developmental delay, early-onset spastic paraplegia and signs of cerebellar volume loss.…”