RESUMEN
Bi-allelic variants affecting one of the four genes encoding the AP4 subunits are responsible for the "AP4 deficiency syndrome." Core features include hypotonia that progresses to hypertonia and spastic paraplegia, intellectual disability, postnatal microcephaly, epilepsy, and neuroimaging features. Namely, AP4M1 (SPG50) is involved in autosomal recessive spastic paraplegia 50 (MIM#612936). We report on three patients with core features from three unrelated consanguineous families originating from the Middle East. Exome sequencing identified the same homozygous nonsense variant: NM_004722.4(AP4M1):c.1012C>T p.Arg338* (rs146262009). So far, four patients from three other families carrying this homozygous variant have been reported worldwide. We describe their phenotype and compare it to the phenotype of patients with other variants in AP4M1. We construct a shared single-nucleotide polymorphism (SNP) haplotype around AP4M1 in four families and suggest a probable founder effect of Arg338* AP4M1 variant with a common ancestor most likely of Turkish origin.
Asunto(s)
Epilepsia , Discapacidad Intelectual , Paraplejía Espástica Hereditaria , Humanos , Discapacidad Intelectual/genética , Mutación/genética , Efecto Fundador , Paraplejía/genética , Paraplejía Espástica Hereditaria/genética , Epilepsia/genética , Linaje , FenotipoRESUMEN
We report on a 6-year-old girl with developmental delay, tall stature, and obesity. G-banded chromosome analysis revealed mosaicism for one to three small de novo rings in 82% of peripheral lymphocytes. Fluorescence in situ hybridization (FISH) studies and metaphase comparative genomic hybridization (CGH) demonstrated that the rings were derived from 4q10-4q13. A higher resolution investigation was initiated using array-CGH analysis and revealed a gain of 11 adjacent clones spanning a 16 Mb region at 4q11-q13.2 and including the insulin-like growth factor binding protein 7 (IGFBP7) gene. This finding suggests that postnatal overgrowth observed in our patient might be related to a dosage effect of the IGFBP7 gene.