Two new cases of interstitial 7q35q36.1 deletion including CNTNAP2 and KMT2C.

BACKGROUND: Terminal deletions of the long arm of chromosome 7 are well known and frequently associated with syndromic holoprosencephaly due to the involvement of the SHH (aliases HHG1, SMMCI, TPT, TPTPS, and MCOPCB5) gene region. However, interstitial deletions including CNTNAP2 (aliases Caspr2, KIAA0868, and NRXN4) and excluding the SHH region are less common. METHODS: We report the clinical and molecular characterization associated with pure 7q35 and 7q35q36.1 deletion in two unrelated patients as detected by oligonucleotide-based array-CGH analysis. RESULTS: The common clinical features were abnormal maternal serum screening during first-trimester pregnancy, low occipitofrontal circumference at birth, hypotonia, abnormal feet, developmental delay, impaired language development, generalized seizures, hyperactive behavior, friendly personality, and cranio-facial dysmorphism. Both deletions occurred de novo and sequencing of CNTNAP2, a candidate gene for epilepsy and autism showed absence of mutation on the contralateral allele. CONCLUSION: Combined haploinsufficiency of GALNTL5 (alias GalNAc-T5L), CUL1, SSPO (aliases SCO-spondin, KIAA0543, and FLJ36112), AOC1 (alias DAO), RHEB, and especially KMT2C (alias KIAA1506 and HALR) with monoallelic disruption of CNTNAP2 may explain neurologic abnormalities, hypotonia, and exostoses. Haploinsufficiency of PRKAG2 (aliases AAKG, AAKG2, H91620p, WPWS, and CMH6) and KCNH2 (aliases Kv11.1, HERG, and erg1) genes may be responsible of long QT syndrome observed for one patient.

Loss of the KH1 domain of FMR1 in humans due to a synonymous variant causes global developmental retardation.

BACKGROUND: Fragile X syndrome (FXS) is a monogenic disorder and a common cause of intellectual disability (ID). Up to now, very few pathological variants other than the typical CGG-repeat expansion have been reported in the FMR1 gene. METHODS: A panel of 56 intellectual disability (ID) genes including the FMR1 gene was sequenced in a cohort of 300 patients with unexplained ID. To determine the effect of a new FMR1 variant, total RNA from peripheral blood cells was reverse transcribed, amplified by polymerase chain reaction and sequenced. RESULTS: We report a novel G to A point variant (c.801G > A) located at the last nucleotide of exon 8 in the FMR1 gene in one patient with ID. Direct sequencing of the RT-PCR products revealed that the transcript from the allele with G to A variant skips exon 8 entirely, resulting in a joining of exons 7 and 9. Skipping of exon 8 may result in an abnormal FMR1 protein (FMRP), which removes the highly conserved region that encoding the KH1 domain of FMRP. CONCLUSIONS: This report describes for the first time that a synonymous variant in the FMR1 gene is associated with an error in mRNA processing, leading preferentially to the production of an aberrant transcript without exon 8. This splice variant was associated with an unspecific clinical presentation, suggesting the need for more detailed investigation of silent variants in ID patients with a large spectrum of phenotypes.