Rett-like phenotypes: expanding the genetic heterogeneity to the KCNA2 gene and first familial case of CDKL5-related disease.

Several genes have been implicated in Rett syndrome (RTT) in its typical and variant forms. We applied next-generation sequencing (NGS) to evaluate for mutations in known or new candidate genes in patients with variant forms of Rett or Rett-like phenotypes of unknown molecular aetiology. In the first step, we used NGS with a custom panel including MECP2, CDKL5, FOXG1, MEF2C and IQSEC2. In addition to a FOXG1 mutation in a patient with all core features of the congenital variant of RTT, we identified a missense (p.Ser240Thr) in CDKL5 in a patient who appeared to be seizure free. This missense was maternally inherited with opposite allele expression ratios in the proband and her mother. In the asymptomatic mother, the mutated copy of the CDKL5 gene was inactivated in 90% of blood cells. We also identified a premature stop codon (p.Arg926*) in IQSEC2 in a patient with a Rett-like phenotype. Finally, exome sequencing enabled us to characterize a heterozygous de novo missense (p.Val408Ala) in KCNA2 encoding the potassium channel Kv 1.2 in a girl with infantile-onset seizures variant of RTT. Our study expands the genetic heterogeneity of RTT and RTT-like phenotypes. Moreover, we report the first familial case of CDKL5-related disease.

Xq28 duplication including MECP2 in six unreported affected females: what can we learn for diagnosis and genetic counselling?

Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases.

Homozygous Truncating Intragenic Duplication in TUSC3 Responsible for Rare Autosomal Recessive Nonsyndromic Intellectual Disability with No Clinical or Biochemical Metabolic Markers.

Intellectual disability (ID), which affects around 2-3% of the general population, is classically divided into syndromic and nonsyndromic forms, with several modes of inheritance. Nonsyndromic autosomal recessive ID (NS-ARID) appears extremely heterogeneous with numerous genes identified to date, including inborn errors of metabolism. The TUSC3 gene encodes a subunit of the endoplasmic reticulum (ER)-bound oligosaccharyltransferase complex, which mediates a key step of N-glycosylation. To date, only five families with NS-ARID and TUSC3 mutations or rearrangements have been reported in the literature. All patients had speech delay, moderate-to-severe ID, and moderate facial dysmorphism. Microcephaly was noted in one third of patients, as was short stature. No patients had congenital malformation except one patient with unilateral cryptorchidism. Glycosylation analyses of patients' fibroblasts showed normal N-glycan synthesis and transfer. We present a review of the 19 patients previously described in the literature and report on a sixth consanguineous family including two affected sibs, with intellectual disability, unspecific dysmorphic features, and no additional malformations identified by high-resolution array-CGH. A homozygous truncating intragenic duplication of the TUSC3 gene leading to an aberrant transcript was detected in two siblings. This observation, which is the first reported case of TUSC3 homozygous duplication, confirms the implication of TUSC3 in NS-ARID and the power of the high-resolution array-CGH in identifying intragenic rearrangements of genes implicated in nonsyndromic ID and rare diseases.

The pituitary stalk interruption syndrome: endocrine features and benefits of growth hormone therapy.

INTRODUCTION: Childhood anterior-pituitary insufficiency has many causes (malformative, genetic, traumatic, tumoral...). One particular entity can be clearly identified: pituitary stalk interruption syndrome (PSIS). The aim of our study was to analyse the long-term evolution of patients with PSIS. PATIENTS AND METHODS: The records of all the children followed at Dijon University Hospital between 1990 and 2008 who underwent brain magnetic resonance imaging (MRI) and endocrinological evaluation that revealed a growth hormone (GH) deficiency were analysed. We thus selected 14 children diagnosed with PSIS according to the results of MRI. We studied the perinatal characteristics of these patients, then the auxological and the endocrine evolutions, before the initiation of GH therapy and then after 1 and 3 years of treatment and during the last evaluation. RESULTS: Fourteen children were diagnosed with PSIS at a mean+/-sd age of 3.2+/-3.5 years, five of whom being diagnosed during the first 2 months of life. Growth, as well as other anterior-pituitary deficiencies, was systematically followed up two to four times a year depending on the clinical context. The results in terms of endocrinology were analysed in all 14 children, and with regard to auxology in the 10 children who received GH therapy for at least 12 months, with a mean of 8.3+/-4.2 years and at a mean maintenance posology of 0.22+/-0.02mg/kg per week. Among the 14 children, 12 had complete GH deficiency while two had a partial deficiency. Nine had multiple anterior pituitary deficiencies, diagnosed at the same time or later in five and four of them respectively. A clinical picture of panhypopituitarism was found in the infants who were diagnosed with PSIS in their first months of life. In the 10 children who were treated for at least 12 months, the height before treatment was -3.1+/-0.8 standard deviation score (SDS). At the last consultation, the total gain in height was +2.5+/-0.9 SDS compared to the distance to target height of +2.7+/-0.6 SDS. The height gain after 1 year of treatment corresponded to 60% of the total gain. CONCLUSION: In children with PSIS, the other anterior pituitary deficiencies are often associated with GH deficiency and sometimes during the first month of life. These functions therefore require to be carefully followed early, periodically and in the long term. Growth in these children responds particularly well to GH therapy, in particular during the first year.