Using whole-exome sequencing, we have identified novel de novo heterozygous pleckstrin homology domain-interacting protein (<i>PHIP</i>) variants that are predicted to be deleterious, including a frameshift deletion, in two unrelated patients with common clinical features of developmental delay, intellectual disability, anxiety, hypotonia, poor balance, obesity, and dysmorphic features.
Our data confirm NDST1 mutations as a cause of autosomal recessive intellectual disability with a distinctive phenotype, and support an important function of NDST1 in human development.
Interestingly, mutations in all four genes (KDM5C, ARX, ZNF711 and PHF8) are associated with X-linked NDDs comprising intellectual disability as a core feature. in vitro analysis of the KDM5C promoter revealed that ARX and ZNF711 function as antagonist transcription factors that activate KDM5C expression and compete for the recruitment of PHF8.
Loss-of-function mutations in the histone demethylases KDM5A, KDM5B, or KDM5C are found in intellectual disability (ID) and autism spectrum disorders (ASD) patients.
Disruption of MED13L, encoding a component of the Mediator complex, is increasingly recognized as the cause of an intellectual disability syndrome with associated facial dysmorphism.
Mutations in <i>KDM5C</i> cause Mental Retardation, X-linked, Syndromic, Claes-Jensen type (MRXSCJ, OMIM #300534) and are one of the most common causes of X-linked ID.
MED13L haploinsufficiency syndrome is a clinical condition manifesting intellectual disability and developmental delay in association with various complications including congenital heart defects and dysmorphic features.
Review of the reported patients with MED13L haploinsufficiency indicates moderate to severe ID and facial anomalies in all patients, as well as severe speech delay and muscular hypotonia in the majority.
We investigated a family of three boys with intellectual disability, and among them we identified two different mutations in KDM5C, located at Xp11.22, using whole-exome sequencing.
Recently, a new syndrome caused by MED13L deleterious variants has been described, which shows similar clinical manifestations including intellectual disability, hypotonia, and other congenital anomalies.
Here, we report on a female patient with severe ID and autistic features carrying a de novo 0.4 Mb deletion containing six coding genes including KDM5C and IQSEC2.
In the ID-linked region at 12q24.22-12q24.31 19 out of 21 ID cases carried segmental CNV and 20 of 21 them displayed ROH segments with mean size lengths for ID cases 2512 kb (500-6,472 kb) and for healthy control 682 kb (531-986 kb), including the genes MED13L, HRK, FBXW8, TESC, CDK2AP1 and SBNO1.