Chromosome region 1q21.1 contains extensive and complex low-copy repeats, and copy number variants (CNVs) in this region have recently been reported in association with congenital heart defects1, developmental delay2,3, schizophrenia and related psychoses4,5. We describe 21 probands with the 1q21.1 microdeletion and 15 probands with the 1q21.1 microduplication. These CNVs were inherited in most of the cases in which parental studies were available. Consistent and statistically significant features of microcephaly and macrocephaly were found in individuals with micro-deletion and microduplication, respectively. Notably, a paralog of the HYDIN gene located on 16q22.2 and implicated in autosomal recessive hydrocephalus6 was inserted into the 1q21.1 region during the evolution of Homo sapiens7; we found this locus to be deleted or duplicated in the individuals we studied, making it a probable candidate for the head size abnormalities observed. We propose that recurrent reciprocal microdeletions and microduplications within 1q21.1 represent previously unknown genomic disorders characterized by abnormal head size along with a spectrum of developmental delay, neuropsychiatric abnormalities, dysmorphic features and congenital anomalies. These phenotypes are subject to incomplete penetrance and variable expressivity.

SUMMARY Complex genomic rearrangements (CGR) consisting of two or more breakpoint junctions have been observed in genomic disorders. Recently, a chromosome catastrophe phenomenon termed chromothripsis, in which numerous genomic rearrangements are apparently acquired in one single catastrophic event, was described in multiple cancers. Here we show that constitutionally acquired CGRs share similarities with cancer chromothripsis. In the 17 CGR cases investigated we observed localization and multiple copy number changes including deletions, duplications and/or triplications, as well as extensive translocations and inversions. Genomic rearrangements involved varied in size and complexities; in one case, array comparative genomic hybridization revealed 18 copy number changes. Breakpoint sequencing identified characteristic features, including small templated insertions at breakpoints and microhomology at breakpoint junctions, which have been attributed to replicative processes. The resemblance between CGR and chromothripsis suggests similar mechanistic underpinnings. Such chromosome catastrophic events appear to reflect basic DNA metabolism operative throughout an organism’s life cycle.

Prader-Willi syndrome (PWS) is caused by deficiency for one or more paternally expressed imprinted transcripts within chromosome 15q11-q13, including SNURF-SNRPN and multiple small nucleolar RNAs (snoRNAs). Balanced chromosomal translocations that preserve expression of SNURF-SNRPN and centromeric genes but separate the snoRNA HBII-85 cluster from its promoter cause PWS. A microdeletion of the HBII-85 snoRNAs in a child with PWS provides, in combination with previous data, effectively conclusive evidence that deficiency of HBII-85 snoRNAs causes the key characteristics of the PWS phenotype, although some atypical features suggest that other genes in the region may make more subtle phenotypic contributions.Large interstitial deletions of paternal origin on chromosome 15q11-q13 are the cause of Prader-Willi syndrome (MIM176270) in ∼70% of cases. Most remaining affected individuals have maternal uniparental disomy 15, and some have imprinting defects. A number of paternally expressed genes mapping within this critical region have been suggested to have a role in the pathogenesis of PWS, including SNURF-SNRPN, which encodes the SNURF and SNRPN polypeptides in a single transcript. Identification of individuals with PWS with balanced translocations leaving the SNURF-SNRPN promoter and coding regions intact later excluded SNURF-SNRPN as a candidate gene 1-4 . Located within the introns of very long transcripts extending downstream of SNRPN, there are clusters of paternally expressed C/D box-containing snoRNAs that are highly expressed in the brain 5,6 . SnoRNAs represent an important subset of noncoding molecules with diverse functions, the best documented being site-specific covalent modifications of ribosomal RNAs and small nuclear RNAs by 2′-Omethylation 5,6 . The translocation cases that exclude SNURF and SNRPN as candidate genes suggest that snoRNA deficiency might cause PWS, but expression of the translocated snoRNAs in the brain could not be tested 3,4 .Here, we describe the characterization of a de novo microdeletion in an individual meeting the criteria for a diagnosis of PWS, showing all of seven major revised clinical criteria including neonatal hypotonia, feeding difficulties and failure to thrive during infancy, excessive weight gain after 18 months, hyperphagia, hypogonadism, global developmental delay and equivocal facial features (Fig. 1 This individual was found to have a deletion in the snoRNA region at 15q11.2 (Fig. 2). Arraybased comparative genomic hybridization (array CGH) using a BAC array showed a loss of copy number for two clones encompassing ∼400 kb within the 15q11-q13 PWS and Angelman Syndrome critical interval ( Supplementary Fig. 1a and Supplementary Methods online). FISH studies with the specific clones suggested a weak but not absent signal ( Supplementary Fig. 1b). To rule out deletion or imprinting abnormalities causing PWS, we carried out DNA methylation analysis of the PWS-imprinting center and found a normal methylation pattern (Fig. 2d). Chromosome analysis showed a norma...

Using whole-exome sequencing, we have identified in ten families 14 individuals with microcephaly, developmental delay, intellectual disability, hypotonia, spasticity, seizures, sensorineural hearing loss, cortical visual impairment, and rare autosomal-recessive predicted pathogenic variants in spermatogenesis-associated protein 5 (SPATA5). SPATA5 encodes a ubiquitously expressed member of the ATPase associated with diverse activities (AAA) protein family and is involved in mitochondrial morphogenesis during early spermatogenesis. It might also play a role in post-translational modification during cell differentiation in neuronal development. Mutations in SPATA5 might affect brain development and function, resulting in microcephaly, developmental delay, and intellectual disability.

Objective Several small case series identified KCTD7 mutations in patients with a rare autosomal recessive disorder designated progressive myoclonic epilepsy (EPM3) and neuronal ceroid lipofuscinosis (CLN14). Despite the name KCTD (potassium channel tetramerization domain), KCTD protein family members lack predicted channel domains. We sought to translate insight gained from yeast studies to uncover disease mechanisms associated with deficiencies in KCTD7 of unknown function. Methods Novel KCTD7 variants in new and published patients were assessed for disease causality using genetic analyses, cell-based functional assays of patient fibroblasts and knockout yeast, and electron microscopy of patient samples. Results Patients with KCTD7 mutations can exhibit movement disorders or developmental regression before seizure onset, and are distinguished from similar disorders by an earlier age of onset. Although most published KCTD7 patient variants were excluded from a genome sequence database of normal human variations, most newly identified patient variants are present in this database, potentially challenging disease causality. However, genetic analysis and impaired biochemical interactions with cullin 3 support a causal role for patient KCTD7 variants, suggesting deleterious alleles of KCTD7 and other rare disease variants may be underestimated. Both patient-derived fibroblasts and yeast lacking Whi2 with sequence similarity to KCTD7 have impaired autophagy consistent with brain pathology. Interpretation Bi-allelic KCTD7 mutations define a neurodegenerative disorder with lipofuscin and lipid droplet accumulation but without defining features of neuronal ceroid lipofuscinosis or lysosomal storage disorders. KCTD7 deficiency appears to cause an underlying autophagy-lysosome defect conserved in yeast, thereby assigning a biological role for KCTD7.