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BackgroundWidespread use of microarray technology has led to increasing identification of 22q11.2 duplication syndrome (22q11.2DupS), the reciprocal syndrome of the well-characterized 22q11.2 deletion syndrome (22q11.2DS). Individuals with 22q11.2DS have elevated rates of community diagnoses of autism spectrum disorder (ASD), schizophrenia, and a range of medical problems and birth defects that necessitate extensive medical screening. Case reports of 22q11.2DupS include patients with ASD, fewer medical problems, and no schizophrenia; however, no prospective cohort study has been reported. The goals of the study were to (1) characterize the neuropsychiatric functioning of a cohort of individuals with 22q11.2DupS in comparison to large samples of typically developing controls (TDCs), ASD and 22q11.2DS; (2) estimate the prevalence of ASD in 22q11.2DupS; (3) determine whether the indications that prompted the genetic testing in 22q11.2DupS differ from 22q11.2DS and (4) determine whether comprehensive medical screening should be recommended for those diagnosed with 22q11.2DupS.MethodsMedical characterization was done by parental questionnaire and medical chart review of individuals with 22q11.2DupS (n = 37) and 22q11.2DS (n = 101). Neuropsychiatric characterization of children with 22.11.2DupS, 22q11.2DS, TDCs, and ASD was done by parent-report questionnaires; in addition, the ASD and 22q11.2DupS groups received the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule.ResultsIndividuals with 22q11.2DupS, 22q11.2DS, and ASD had significantly impaired social interaction and adaptive behavior skills compared to TDCs. Overall, 38 % of children aged 2–18 with 22q11.2DupS had community diagnoses of ASD, but fewer (14–25 %) met on the basis of best clinical judgment that included ADI-R and ADOS data. Indications for genetic testing were significantly different for 22q11.2DupS and 22q11.2DS, with the deletions more commonly tested because of birth defects or medical problems, and the duplications because of developmental delay. However, when the screening protocol for 22q11.2DS was applied to the 22q11.2DupS sample, several medical problems were identified that would pose significant risk if left undetected.Conclusions22q11.2DupS has a high rate of ASD at 14–25 %, among the highest of any genetic disorder. Prospective medical screening should be done for all patients with 22q11.2DupS, including those diagnosed due to developmental delays and ASD alone.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-016-0090-z) contains supplementary material, which is available to authorized users.

SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.

Central conducting lymphatic anomaly (CCLA) is one of the complex lymphatic anomalies characterized by dilated lymphatic channels, lymphatic channel dysmotility and distal obstruction affecting lymphatic drainage. We performed whole exome sequencing (WES) of DNA from a four-generation pedigree and examined the consequences of the variant by transfection of mammalian cells and morpholino and rescue studies in zebrafish. WES revealed a heterozygous mutation in EPHB4 (RefSeq NM_004444.4; c.2334 + 1G>C) and RNA-Seq demonstrated that the EPHB4 mutation destroys the normal donor site, which leads to the use of a cryptic splice donor that results in retention of the intervening 12-bp intron sequence. Transient co-expression of the wild-type and mutant EPHB4 proteins showed reduced phosphorylation of tyrosine, consistent with a loss-of-function effect. Zebrafish ephb4a morpholino resulted in vessel misbranching and deformities in the lymphatic vessel development, indicative of possible differentiation defects in lymphatic vessels, mimicking the lymphatic presentations of the patients. Immunoblot analysis using zebrafish lysates demonstrated over-activation of mTORC1 as a consequence of reduced EPHB4 signaling. Strikingly, drugs that inhibit mTOR signaling or RAS-MAPK signaling effectively rescued the misbranching phenotype in a comparable manner. Moreover, knock-in of EPHB4 mutation in HEK293T cells also induced mTORC1 activity. Our data demonstrate the pathogenicity of the identified EPHB4 mutation as a novel cause of CCLA and suggesting that ERK inhibitors may have therapeutic benefits in such patients with complex lymphatic anomalies.

Objective: Certain copy number variants (CNVs) greatly increase risk of autism. We conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships.Methods: This international study included 566 children (12.3 years (SD=4.2), 51% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (83 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 380 22q11.2 deletion carriers and 53 22q11.2 duplication carriers), as well as 2027 children (9.1 years (SD=4.9), 87% male) with autism of heterogeneous aetiology. The Autism Diagnostic Interview-Revised (ADI-R) and IQ testing were conducted. Results:The four genetic variant groups differed in autism severity, autism subdomain profile as well as IQ profile. However, we found substantial variability in phenotypic outcome within individual genetic variant groups (75% to 96% of the variance depending on the trait), whereas variability between groups was low (1% to 21% depending on trait). We compared CNV carriers who met autism criteria, to children with heterogeneous autism, and a range of profile differences were identified. Using clinical cut-offs, we found that 54% of children with one of the 4CNVs who did not meet full autism diagnostic criteria nonetheless had elevated levels of autistic traits. Conclusion:Many CNV carriers do not meet full diagnostic criteria for autism, but nevertheless meet clinical cut-offs for autistic traits. Although we find profile differences between variants, there is considerable variability in clinical symptoms within the same variant..

In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.

BackgroundPrevious studies have reported no clear critical region for medical comorbidities in children with deletions or duplications of 22q11.2. The purpose of this study was to evaluate whether individuals with small nested deletions or duplications of the LCR-A to B region of 22q11.2 show an elevated rate of autism spectrum disorder (ASD) compared to individuals with deletions or duplications that do not include this region.MethodsWe recruited 46 patients with nested deletions (n = 33) or duplications (n = 13) of 22q11.2, including LCR-A to B (n del = 11), LCR-A to C (n del = 4), LCR-B to D (n del = 14; n dup = 8), LCR-C to D (n del = 4; n dup = 2), and smaller nested regions (n = 3). Parent questionnaire, record review, and, for a subset, in-person evaluation were used for ASD diagnostic classification. Rates of ASD in individuals with involvement of LCR-B to LCR-D were compared with Fisher’s exact test to LCR-A to LCR-B for deletions, and to a previously published sample of LCR-A to LCR-D for duplications. The rates of medical comorbidities and psychiatric diagnoses were determined from questionnaires and chart review. We also report group mean differences on psychiatric questionnaires.ResultsIndividuals with deletions involving LCR-A to B showed a 39–44% rate of ASD compared to 0% in individuals whose deletions did not involve LCR-A to B. We observed similar rates of medical comorbidities in individuals with involvement of LCR-A to B and LCR-B to D for both duplications and deletions, consistent with prior studies.ConclusionsChildren with nested deletions of 22q11.2 may be at greater risk for autism spectrum disorder if the region includes LCR-A to LCR-B. Replication is needed.Electronic supplementary materialThe online version of this article (10.1186/s13229-017-0171-7) contains supplementary material, which is available to authorized users.