Background: Intellectual disability (ID) is a common neurodevelopmental disorder affecting 1–3% of the general population. Mutations in more than 10% of all human genes are considered to be involved in this disorder, although the majority of these genes are still unknown. Objectives: We investigated 19 small non-consanguineous families with two to five affected siblings in order to identify pathogenic gene variants in known, novel and potential ID candidate genes. Non-consanguineous families have been largely ignored in gene identification studies as small family size precludes prior mapping of the genetic defect. Methods and results: Using exome sequencing, we identified pathogenic mutations in three genes, DDHD2, SLC6A8, and SLC9A6, of which the latter two have previously been implicated in X-linked ID phenotypes. In addition, we identified potentially pathogenic mutations in BCORL1 on the X-chromosome and in MCM3AP, PTPRT, SYNE1, and ZNF528 on autosomes. Conclusions: We show that potentially pathogenic gene variants can be identified in small, non-consanguineous families with as few as two affected siblings, thus emphasising their value in the identification of syndromic and non-syndromic ID genes.

The interstitial 6p deletions, involving the 6p22-p24 chromosomal region, are rare events characterized by variable phenotypes and no clear genotype-phenotype correlation has been established so far.

Recessive mutations in the POLR3A gene cause POLR3-HLD (the second-most-common form of childhood-onset hypomyelinating leukodystrophy), a neurodegenerative disorder featuring deficient cerebral myelin formation. To date, more than 140 POLR3A (NM_007055.3) missense mutations are related to the pathogenesis of POLR3-related leukodystrophy and spastic ataxia. Herein, in a cohort of five families from Sicily (Italy), we detected two cases of patients affected by POLR3-related leukodystrophy, one due to a compound heterozygous mutation in the POLR3A gene, including a previously undescribed missense mutation (c.328A > G (p.Lys110Glu)). Our study used an in-house NGS gene panel comprising 41 known leukodystrophy genes. Successively, we used a predictive test supporting the missense mutation as causative of disease, thus this mutation can be considered “Likely Pathogenic” and could be as a new pathogenetic mutation of the POLR3A gene causing a severe form of POLR3-HLD.

Background: Hereditary spastic paraparesis (HPS) linked to mutations in the spastin gene (SPG4) is considered to be a pure form of spastic hereditary paraparesis. However, in this disease also other signs of central nervous system involvement are frequently found. Methods: Clinical, genetical and neuroradiological investigations were carried out in a large family with autosomal dominant spastic paraparesis and in a sporadic case with spastic paraparesis. Results: Additional clinical and molecular data are provided, studying other members of the same pedigree, as already described, with a five-base deletion in exon 9 of the SPG4 gene (1215–1219delTATAA) whose members show MRI anomalies that fall within the Dandy–Walker continuum. Furthermore, an unrelated female patient with hypoplasia of the cerebellar vermis is indicated, carrying a de novo previously reported mutation of the SPG4 gene (c.1741C>T p.R581X). Conclusions: Spastin may play an important role in the development of the central nervous system and in particular in the development of the structures of posterior fossa.