Novel homozygous mutation in KPTN gene causing a familial intellectual disability‐macrocephaly syndrome

Abstract

Recently, a novel autosomal recessive developmental delay-macrocephaly syndrome was described caused by homozygous or compound heterozygous mutations in the KPTN gene. All reported patients belonged to one large Amish kindred. We report on the second case of KPTN-related syndrome in two Estonian adult sibs. The brother and sister both have macrocephaly and moderate intellectual disability, and their verbal abilities are more affected than motor development. No notable minor anomalies are present. Behavioral problems and a few episodes of seizures were reported in the brother. Whole exome sequencing carried out from the brother's DNA sample identified homozygous one-nucleotide frameshift duplication c.665dupA (p.Q222fs) in the KPTN gene. Homozygosity of both affected sibs and heterozygosity of parents were confirmed by Sanger sequencing. Thus, we confirm the pathogenicity of KPTN mutations and further delineate the novel developmental delay-macrocephaly syndrome. We also support the hypothesis that KPTN-related syndrome is not restricted to the Amish population.

KPTN gene homozygous variant‐related syndrome in the northeast of Brazil: A case report

“…When comparing clinical characteristics among the cases reported by Baple et al (2014), Pajusalu et al (2015), Thiffault et al (2018) and the current study, some differences can be found. For instance, hooded eyelids, broad nasal tip, and fifth finger clinodactyly were only found by Baple et al (2014) and self-aggression was only reported by Pajusalu et al (2015). On the other hand, macrocephaly, frontal bossing, stomatognathic alterations, delayed psychomotor development, intellectual disability, and speech deficits were found in all four reports.…”

“…Moreover, two similar cases in Estonian siblings were also reported, suggesting that the condition was not restricted to the Amish community and that different variants within KPTN can lead to resembling phenotypes (Pajusalu, Remand, & Õunap, ). Table shows clinical manifestations of KPTN gene variation as reported in the literature.…”

“…In 2015, it was described a case of two siblings that share similar characteristics to the ones identified in the Amish community. They concluded that cardinal features for that mutation are macrocephaly and intellectual disability (Pajusalu et al, ). Similar to the child described in our case report, the Estonians siblings also presented language, intellectual and motor disability.…”

The Diagnostic Utility of Single Long Contiguous Stretches of Homozygosity in Patients without Parental Consanguinity

“…Of these 7 patients, 2 received a definitive diagnosis by WES ( table 3 ). First, WES in an adult man with ID and macrocephaly (reported in detail by us [Pajusalu et al, 2015]) revealed a homozygous 1-bp duplication in the KPTN gene (19q13.32) which is associated with such a phenotype [Baple et al, 2014]. The patient also has a sister with a similar phenotype who carried the same homozygous mutation.…”

“…We also referred to a previously published case, in which a shared LCSH was discovered in an adult man and his sister, and in which subsequent WES led to the discovery of a homozygous pathogenic mutation outside the shared LCSH [Pajusalu et al, 2015]. Nevertheless, reevaluating the CMA data of the sibs revealed a small 1.5-Mb LCSH in the region of the pathogenic mutation.…”