Benjamin Kamien

Characterization of a 520 kb deletion on chromosome 15q26.1 including ST8SIA2 in a patient with behavioral disturbance, autism spectrum disorder, and epilepsy

We present a patient with a behavioral disorder, epilepsy, and autism spectrum disorder who has a 520 kb chromosomal deletion at 15q26.1 encompassing three genes: ST8SIA2, C15orf32, and FAM174B. Alpha‐2,8‐Sialyltransferase 2 (ST8SIA2) is expressed in the developing brain and appears to play an important role in neuronal migration, axon guidance and synaptic plasticity. It has recently been implicated in a genome wide association study as a potential factor underlying autism, and has also been implicated in the pathogenesis of bipolar disorder and schizophrenia. This case provides supportive evidence that ST8SIA2 haploinsufficiency may play a role in neurobehavioral phenotypes.

Genotype and clinical care correlations in craniosynostosis: Findings from a cohort of 630 Australian and New Zealand patients

Craniosynostosis is one of the most common craniofacial disorders encountered in clinical genetics practice, with an overall incidence of 1 in 2,500. Between 30% and 70% of syndromic craniosynostoses are caused by mutations in hotspots in the fibroblast growth factor receptor (FGFR) genes or in the TWIST1 gene with the difference in detection rates likely to be related to different study populations within craniofacial centers. Here we present results from molecular testing of an Australia and New Zealand cohort of 630 individuals with a diagnosis of craniosynostosis. Data were obtained by Sanger sequencing of FGFR1, FGFR2, and FGFR3 hotspot exons and the TWIST1 gene, as well as copy number detection of TWIST1. Of the 630 probands, there were 231 who had one of 80 distinct mutations (36%). Among the 80 mutations, 17 novel sequence variants were detected in three of the four genes screened. In addition to the proband cohort there were 96 individuals who underwent predictive or prenatal testing as part of family studies. Dysmorphic features consistent with the known FGFR1‐3/TWIST1‐associated syndromes were predictive for mutation detection. We also show a statistically significant association between splice site mutations in FGFR2 and a clinical diagnosis of Pfeiffer syndrome, more severe clinical phenotypes associated with FGFR2 exon 10 versus exon 8 mutations, and more frequent surgical procedures in the presence of a pathogenic mutation. Targeting gene hot spot areas for mutation analysis is a useful strategy to maximize the success of molecular diagnosis for individuals with craniosynostosis.

Outfoxed by RBFOX1-A caution about ascertainment bias

We report on two patients with intragenic deletions of RBFOX1 and one patient with an intragenic duplication of RBFOX1. These patients, by report, all had autism spectrum disorder and/or developmental delay and had strong family histories of these conditions. We initially hypothesized that RBFOX1 was another susceptibility locus for autism spectrum disorder or developmental delay. However, epidemiological evidence examining large numbers of individuals did not support this hypothesis and the data presented here suggests that RBFOX1 intragenic copy number variants are not pathogenic. This contradicts previous reports that examined smaller numbers of patients and controls.

Expanding the mutational spectrum of CRLF1 in Crisponi/CISS1 syndrome.

Crisponi syndrome (CS) and cold‐induced sweating syndrome type 1 (CISS1) share clinical characteristics, such as dysmorphic features, muscle contractions, scoliosis, and cold‐induced sweating, with CS patients showing a severe clinical course in infancy involving hyperthermia associated with death in most cases in the first years of life. To date, 24 distinct CRLF1 mutations have been found either in homozygosity or in compound heterozygosity in CS/CISS1 patients, with the highest prevalence in Sardinia, Turkey, and Spain. By reporting 11 novel CRLF1 mutations, here we expand the mutational spectrum of CRLF1 in the CS/CISS1 syndrome to a total of 35 variants and present an overview of the different molecular and clinical features of all of them. To catalog all the 35 mutations, we created a CRLF1 mutations database, based on the Leiden Open (source) Variation Database (LOVD) system (https://grenada.lumc.nl/LOVD2/mendelian_genes/variants). Overall, the available functional and clinical data support the fact that both syndromes actually represent manifestations of the same autosomal‐recessive disorder caused by mutations in the CRLF1 gene. Therefore, we propose to rename the two overlapping entities with the broader term of Crisponi/CISS1 syndrome.

A familial 7q36.3 duplication associated with agenesis of the corpus callosum

Small chromosomal duplications involving 7q36.3 have rarely been reported. This clinical report describes four individuals from a three‐generation family with agenesis of the corpus callosum (ACC) and a 0.73 Mb duplication of 7q36.3 detected by array CGH. The 7q36.3 duplication involves two genes: RNA Binding Motif Protein 33 (RBM33) and Sonic Hedgehog (SHH). Most affected family members had mild intellectual disability or borderline intellectual functioning, macrocephaly, a broad forehead, and widely spaced eyes. Two individuals had a Chiari type I malformation. This is the first family reported with ACC associated with a small duplication of these genes. While we cannot establish causation for the relationship between any single gene and the ACC in this family, there is a role for SHH in the formation of the corpus callosum through correct patterning and assembly of the commissural plate, and these data concur with vertebrate studies showing that a gain of SHH expands the facial primordium.

Characterization of a 520 kb deletion on chromosome 15q26.1 including ST8SIA2 in a patient with behavioral disturbance, autism spectrum disorder, and epilepsy: additional information.

Characterization of a 520 kb deletion on chromosome 15q26.1 including ST8SIA2 in a patient with behavioral disturbance, autism spectrum disorder, and epilepsy: Additional information Benjamin Kamien,* James Harraway, Ben Lundie, Lex Smallhorne, Vicki Gibbs, Anna Heath, and Janice M. Fullerton Hunter Genetics, Newcastle, New South Wales, Australia School of Medicine and Public Health, The University of Newcastle, Newcastle, New South Wales, Australia Sullivan Nicolaides Pathology, Brisbane, Queensland, Australia Autism Spectrum Australia, Sydney, New South Wales, Australia Neuroscience Research Australia, Sydney, New South Wales, Australia School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia

Septo-optic dysplasia and associations with amyoplasia and gastroschisis.

BACKGROUND The causes of septo-optic dysplasia, amyoplasia, and gastroschisis are mostly unknown. CASES We present a patient with septo-optic dysplasia and amyoplasia. We also present a patient with features of septo-optic dysplasia, gray matter heterotopias, and gastroschisis. CONCLUSIONS These previously unreported combinations provide further support for vascular disruption in embryonic or fetal life as an etiological factor in these conditions.

Narrowing the critical region for overgrowth within 13q14.2-q14.3 microdeletions.

Large chromosomal deletions from 13q13.3 to 13q21.3 have previously been associated with overgrowth. We present two patients with deletions at 13q14.2q14.3 who have macrocephaly, tall stature relative to their parents, cardiac phenotypes, and intellectual disability. This report narrows the critical region for tall stature, macrocephaly, and possibly cardiac disease.

Atypical Angelman syndrome due to a mosaic imprinting defect: Case reports and review of the literature

Angelman syndrome (AS) is characterized by severe intellectual disability, limited, or absent speech and a generally happy demeanor. The four known etiological mechanisms; deletions, uniparental disomy, imprinting defects, and UBE3A mutation all affect expression of the UBE3A gene at 15q11‐q13. An atypical phenotype is seen in individuals who are mosaic for a chromosome 15q11‐q13 imprinting defect on the maternal allele. These patients present with a milder phenotype, often with hyperphagia and obesity or non‐specific intellectual disability. Unlike typical AS syndrome, they can have a vocabulary up to 100 words and speak in sentences. Ataxia and seizures may not be present, and the majority of individuals do not have microcephaly. Here we review the current literature and present three individuals with atypical AS caused by a mosaic imprinting defect to demonstrate why DNA methylation analysis at the SNRPN locus needs to be considered in a broader clinical context.

Aicardi syndrome associated with hepatoblastoma and pulmonary sequestration

We present a female with Aicardi syndrome (AS) who had infantile spasms, characteristic chorioretinal lacunae, partial agenesis of the corpus callosum, and neuronal migration abnormalities. Our patient was also diagnosed with a composite lung lesion of intralobar pulmonary sequestration and congenital cystic adenomatoid malformation (CCAM) and developed a hepatoblastoma. This is the second report that describes the association of hepatoblastoma and AS, and the first report of pulmonary sequestration or CCAM and AS...