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PurposeNuclear receptor binding SET domain protein 1, NSD1, encodes a histone methyltransferase H3K36. NSD1 is responsible for the phenotype of the reciprocal 5q35.2q35.3 microdeletion-microduplication syndromes. We expand the phenotype and demonstrate the functional role of NSD1 in microduplication 5q35 syndrome.MethodsThrough an international collaboration, we report nine new patients, contributing to the emerging phenotype, highlighting psychiatric phenotypes in older affected individuals. Focusing specifically on the undergrowth phenotype, we have modeled the effects of Mes-4/NSD overexpression in Drosophila melanogaster.ResultsThe individuals (including a family) from diverse backgrounds with duplications ranging in size from 0.6 to 4.5 Mb, have a consistent undergrowth phenotype. Mes-4 overexpression in the developing wing causes undergrowth, increased H3K36 methylation, and increased apoptosis. We demonstrate that altering the levels of insulin receptor (IR) rescues the apoptosis and the wing undergrowth phenotype, suggesting changes in mTOR pathway signaling. Leucine supplementation rescued Mes-4/NSD induced cell death, demonstrating decreased mTOR signaling caused by NSD1.ConclusionGiven that we show mTOR inhibition as a likely mechanism and amelioration of the phenotype by leucine supplementation in a fly model, we suggest further studies should evaluate the therapeutic potential of leucine or branched chain amino acids as an adjunct possible treatment to ameliorate human growth and psychiatric phenotypes and propose inclusion of 5q35-microduplication as part of the differential diagnosis for children and adults with delayed bone age, short stature, microcephaly, developmental delay, and psychiatric phenotypes.

Background:The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation.Aim:We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome.Results:We estimate the prevalence of the syndrome to be 1 in 16 000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729–41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10−5).Conclusion:Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.

Submicroscopic deletions involving chromosome 1q43–q44 result in cognitive impairment, microcephaly, growth restriction, dysmorphic features, and variable involvement of other organ systems. A consistently observed feature in patients with this deletion are the corpus callosal abnormalities (CCAs), ranging from thinning and hypoplasia to complete agenesis. Previous studies attempting to delineate the critical region for CCAs have yielded inconsistent results. We conducted a detailed clinical and molecular characterization of seven patients with deletions of chromosome 1q43–q44. Using array comparative genomic hybridization, we mapped the size, extent, and genomic content of these deletions. Four patients had CCAs, and shared the smallest region of overlap that contains only three protein coding genes, CEP170 , SDCCAG8 , and ZNF238 . One patient with a small deletion involving SDCCAG8 and AKT3 , and another patient with an intragenic deletion of AKT3 did not have any CCA, implying that the loss of these two genes is unlikely to be the cause of CCA. CEP170 is expressed extensively in the brain, and encodes for a protein that is a component of the centrosomal complex. ZNF238 is involved in control of neuronal progenitor cells and survival of cortical neurons. Our results rule out the involvement of AKT3 , and implicate CEP170 and/or ZNF238 as novel genes causative for CCA in patients with a terminal 1q deletion.

Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited multisystem developmental disorder characterized by growth and cognitive retardation; abnormalities of the upper limbs; gastroesophageal dysfunction; cardiac, ophthalmologic and genitourinary anomalies; hirsutism; and characteristic facial features 1 , 2 , 3 . Genital anomalies, pyloric stenosis, congenital diaphragmatic hernias, cardiac septal defects, hearing loss and autistic and self-injurious tendencies also frequently occur 2 . Prevalence is estimated to be as high as 1 in 10,000 (ref. 4 ). We carried out genome-wide linkage exclusion analysis in 12 families with CdLS and identified four candidate regions, of which chromosome 5p13.1 gave the highest multipoint lod score of 2.7. This information, together with the previous identification of a child with CdLS with a de novo t(5;13)(p13.1;q12.1) translocation, allowed delineation of a 1.1-Mb critical region on chromosome 5 for the gene mutated in CdLS. We identified mutations in one gene in this region, which we named NIPBL , in four sporadic and two familial cases of CdLS. We characterized the genomic structure of NIPBL and found that it is widely expressed in fetal and adult tissues. The fly homolog of NIPBL , Nipped-B, facilitates enhancer-promoter communication and regulates Notch signaling and other developmental pathways in Drosophila melanogaster 5 .

BackgroundChitayat-Hall syndrome, initially described in 1990, is a rare condition characterised by distal arthrogryposis, intellectual disability, dysmorphic features and hypopituitarism, in particular growth hormone deficiency. The genetic aetiology has not been identified.Methods and resultsWe identified three unrelated families with a total of six affected patients with the clinical manifestations of Chitayat-Hall syndrome. Through whole exome or whole genome sequencing, pathogenic variants in the MAGEL2 gene were identified in all affected patients. All disease-causing sequence variants detected are predicted to result in a truncated protein, including one complex variant that comprised a deletion and inversion.ConclusionsChitayat-Hall syndrome is caused by pathogenic variants in MAGEL2 and shares a common aetiology with the recently described Schaaf-Yang syndrome. The phenotype of MAGEL2-related disorders is expanded to include growth hormone deficiency as an important and treatable complication.

Osteopathia striata with cranial sclerosis (OSCS) is an X-linked dominant condition characterised by metaphyseal striations, macrocephaly, cleft palate, and developmental delay in affected females. Males have a more severe phenotype with multi-organ malformations, and rarely survive. To date, only frameshift and nonsense variants in exon 2, the single coding exon of AMER1, or whole gene deletions have been reported to cause OSCS. In this study, we describe two families with phenotypic features typical of OSCS. Exome sequencing and multiplex ligation-dependent probe amplification (MLPA) did not identify pathogenic variants in AMER1. Therefore, genome sequencing was employed which identified two deletions containing the non-coding exon 1 of AMER1 in the families. These families highlight the importance of considering variants or deletions of upstream non-coding exons in conditions such as OSCS, noting that often such exons are not captured on probe or enrichment-based platforms because of their high G/C content.

Once, as a hospital volunteer, she lost her lunch while watching a percutaneous needle biopsy of a coin lesion of the lung through a window in the fluoroscopy suite. She did not know what a biopsy was. She did not care about the lethal prognosis of a coin lesion. She only worried whether this incident would prevent her from getting into medical school. Once, on duty in the emergency department, she saw a 17-year-old girl's leftpupil dilate and her lefteye deviate down and outward, and she knew that an artery inside the girl's brain had just hemorrhaged and was killing her. She wanted to crack open the girl's skull to relieve the pressure, to let the blood out, to allow the brainstem to spring back to normal, but she called the code instead and the cardiac-arrest team pushed her aside as the girl died.

Purpose To assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants. Methods We analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants. Results The number of rare likely deleterious variants in functionally intolerant genes (“other hits”) correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion ( n =23, p =0.004) and in autism probands carrying gene-disruptive variants ( n =184, p =0.03) compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features ( p =0.04) and higher burden of other hits compared with those with mild/no family history ( p =0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs ( n =53) or de novo pathogenic variants in disease genes ( n =290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5 , AUTS2 , and NRXN1 , and were enriched for cellular and developmental processes. Conclusion Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.

Interstitial deletions of the short arm of chromosome 6 are rare and have been associated with developmental delay, hypotonia, congenital anomalies, and dysmorphic features. We used array comparative genomic hybridization in a South Carolina Autism Project (SCAP) cohort of 97 subjects with autism spectrum disorders (ASDs) and identified an ~ 5.4 Mb deletion on chromosome 6p22.3-p23 in a 15-year-old patient with intellectual disability and ASDs. Subsequent database queries revealed five additional individuals with overlapping submicroscopic deletions and presenting with developmental and speech delay, seizures, behavioral abnormalities, heart defects, and dysmorphic features. The deletion found in the SCAP patient harbors ATXN1 , DTNBP1 , JARID2 , and NHLRC1 that we propose may be responsible for ASDs and developmental delay.