Joyce So

Encoding of human basic and glycosylated proline-rich proteins by the PRB gene complex and proteolytic processing of their precursor proteins

Proline-rich proteins (PRPs) constitute a family of about 20 members in human saliva that are encoded by six genes. Assignment of genomic DNA coding regions is complicated because of the occurrence of many alleles and the great similarity of amino acid sequences of PRPs. To overcome these problems, the nucleotide sequences of the genes encoding basic and glycosylated PRPs from one person were determined and then aligned with her previously determined protein sequences. This, together with additional protein data, has also resolved various discrepancies between corresponding protein and DNA sequences. For the first time in one person it is now possible to account for all the regions in the PRB genes encoding basic and glycosylated PRPs, and the primary structures of all secreted basic and glycosylated PRPs have been determined. Each gene encodes a precursor protein that subsequently undergoes proteolytic cleavage, thereby giving rise to the secreted proteins. The results have allowed identification of all the proteolytic cleavage sites in the precursor proteins, which all conform to a consensus cleavage site for furin. To evaluate if furin is responsible for the precursor protein cleavages, a recombinant precursor protein was synthesized by in vitro transcription translation of a PRB1 allele. The protein was shown to be correctly cleaved by furin, giving rise to the expected secreted proteins.

De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.

Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS‐like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of 16 patients with CdLS‐like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant‐negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3‐associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects, and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for ∼1%–2% of CdLS‐like phenotypes.

Deletion of 15q11.2(BP1‐BP2) region: Further evidence for lack of phenotypic specificity in a pediatric population

Microdeletion of the BP1‐BP2 region at 15q11.2 is a recurrent copy number variant (CNV) frequently found in patients undergoing chromosomal microarray (CMA). Genetic counselling regarding this CNV is challenging due to the wide range of phenotypic presentation in reported patients and lack of general population‐based data. As one of the most common reasons for CMA is childhood developmental delay, clinicians need to be cognizant of the inherent ascertainment bias in the literature. We performed a detailed medical record review for 55 patients with this 15q11.2 microdeletion and report the clinical features of the 35 patients for whom information was available. We compared our results to the recent report by Cafferkey et al. in this journal. Our conclusion is that the phenotypic spectrum is too broad and non‐specific to constitute a bona fide “syndrome” and that further research must be done to delineate the contribution of this CNV to phenotype.

Periventricular nodular heterotopia and transverse limb reduction defect in a woman with interstitial 11q24 deletion in the Jacobsen syndrome region

Jacobsen syndrome (JS) is a disorder of developmental delay, growth retardation, thrombocytopenia, dysmorphic features, and cardiac abnormalities, among other congenital anomalies. JS is caused by contiguous gene deletion in distal chromosome 11q, generally varying in size from 7 to 20 Mb. Periventricular nodular heterotopia (PVNH) is a neuronal migration disorder in which neurons are abnormally located in nodules along the edges of the lateral ventricles. PVNH can also be seen with other congenital anomalies, including a recurrent association with distal limb defects. Transverse limb defects have previously been reported in two patients with JS. We report on a patient with a 3.162 Mb interstitial deletion at chromosome region 11q24 overlapping the region commonly affected in JS. The patient had PVNH and a transverse limb reduction defect, with minimal typical findings of JS. This is the first report of PVNH associated with a microdeletion at chromosome 11q and may represent an expansion of the phenotypic spectrum associated with JS. This is the third report of transverse limb reduction defects in association with JS, supporting a widening of the skeletal phenotypic spectrum in JS to include more severe limb anomalies. ETS1 is proposed as a candidate gene for involvement in limb anomalies in JS.

Truncation of the E3 ubiquitin ligase component FBXO31 causes non-syndromic autosomal recessive intellectual disability in a Pakistani family

In this study, we have performed autozygosity mapping on a large consanguineous Pakistani family segregating with intellectual disability. We identified two large regions of homozygosity-by-descent (HBD) on 16q12.2–q21 and 16q24.1–q24.3. Whole exome sequencing (WES) was performed on an affected individual from the family, but initially, no obvious mutation was detected. However, three genes within the HBD regions that were not fully captured during the WES were Sanger sequenced and we identified a five base pair deletion (actually six base pairs deleted plus one base pair inserted) in exon 7 of the gene FBXO31. The variant segregated completely in the family, in recessive fashion giving a LOD score of 3.95. This variant leads to a frameshift and a premature stop codon and truncation of the FBXO31 protein, p.(Cys283Asnfs*81). Quantification of mRNA and protein expression suggests that nonsense-mediated mRNA decay also contributes to the loss of FBXO31 protein in affected individuals. FBXO31 functions as a centrosomal E3 ubiquitin ligase, in association with SKP1 and Cullin-1, involved in ubiquitination of proteins targeted for degradation. The FBXO31/SKP1/Cullin1 complex is important for neuronal morphogenesis and axonal identity. FBXO31 also plays a role in dendrite growth and neuronal migration in developing cerebellar cortex. Our finding adds further evidence of the involvement of disruption of the protein ubiquitination pathway in intellectual disability.

A detailed clinical analysis of 13 patients with AUTS2 syndrome further delineates the phenotypic spectrum and underscores the behavioural phenotype

Background AUTS2 syndrome is an ‘intellectual disability (ID) syndrome’ caused by genomic rearrangements, deletions, intragenic duplications or mutations disrupting AUTS2. So far, 50 patients with AUTS2 syndrome have been described, but clinical data are limited and almost all cases involved young children. Methods We present a detailed clinical description of 13 patients (including six adults) with AUTS2 syndrome who have a pathogenic mutation or deletion in AUTS2. All patients were systematically evaluated by the same clinical geneticist. Results All patients have borderline to severe ID/developmental delay, 83–100% have microcephaly and feeding difficulties. Congenital malformations are rare, but mild heart defects, contractures and genital malformations do occur. There are no major health issues in the adults; the oldest of whom is now 59 years of age. Behaviour is marked by it is a friendly outgoing social interaction. Specific features of autism (like obsessive behaviour) are seen frequently (83%), but classical autism was not diagnosed in any. A mild clinical phenotype is associated with a small in-frame 5′ deletions, which are often inherited. Deletions and other mutations causing haploinsufficiency of the full-length AUTS2 transcript give a more severe phenotype and occur de novo. Conclusions The 13 patients with AUTS2 syndrome with unique pathogenic deletions scattered around the AUTS2 locus confirm a phenotype–genotype correlation. Despite individual variations, AUTS2 syndrome emerges as a specific ID syndrome with microcephaly, feeding difficulties, dysmorphic features and a specific behavioural phenotype.

The expanding phenotypic spectrum of female SLC9A6 mutation carriers: a case series and review of the literature

Christianson syndrome (OMIM 300243), caused by mutations in the X-linked SLC9A6 gene, is characterized by severe global developmental delay and intellectual disability, developmental regression, epilepsy, microcephaly and impaired ocular movements. It shares many common features with Angelman syndrome. Carrier females have been described as having learning difficulties with mild to moderate intellectual disability, behavioural issues and psychiatric illnesses. There is little literature on the carrier female phenotype of Christianson syndrome. We describe a large extended family with three affected males, four carrier females, one presumed carrier female and one obligate carrier female with a c.190G>T, p.E64X mutation known to cause a premature stop codon in SLC9A6. We characterize and expand the clinical phenotype of female SLC9A6 mutation carriers by comparing our described family with female carriers previously discussed in the literature. In particular, we highlight the neurodevelopmental and psychiatric phenotypes observed in our family and previous reports.

Enrichment of gene variants associated with treatable genetic disorders in psychiatric populations

Purpose Many genetic conditions can mimic mental health disorders, with psychiatric symptoms that are difficult to treat with standard psychotropic medications. This study tests the hypothesis that psychiatric populations are enriched for pathogenic variants associated with selected treatable genetic disorders. Methods Using next-generation sequencing, 2046 psychiatric patients were screened for variants in genes associated with four inborn errors of metabolism (IEMs), Niemann-Pick disease type C (NPC), Wilson disease (WD), homocystinuria (HOM), and acute intermittent porphyria (AIP). Results Among the 2046 cases, carrier rates of 0·83%, 0·98%, 0·20%, and 0·24% for NPC, WD, HOM, and AIP were seen respectively. An enrichment of known and likely pathogenic variants in the genes associated with NPC and AIP was found in the psychiatric cohort, and especially in schizophrenia patients. Conclusion The results of this study support that rare genetic disease variants, such as those associated with IEMs, may contribute to the pathogenesis of psychiatric disorders. IEMs should be considered as possible causative factors for psychiatric presentations, especially in psychotic disorders, such as schizophrenia, and in the context of poor treatment response.

Oculoleptomeningeal Amyloidosis Secondary to the Rare Transthyretin c.381T>G (p.Ile127Met) Mutation

BACKGROUND Oculoleptomeningeal amyloidosis (OLMA) represents a rare subtype of familial transthyretin (TTR) amyloidosis, characterized by deposition of amyloid in cranial and spinal leptomeninges along with ocular involvement. Of >100 TTR mutations identified, few have been associated with OLMA. Herein we describe the first report of leptomeningeal amyloidosis associated with the c.381T>G (p.Ile127Met) TTR mutation, linking this variant to the OLMA phenotype. CASE DESCRIPTION A 53 year-old man presented with a 2-year history of progressive symptoms including upper and lower limb weakness, ataxia, and peripheral and autonomic neuropathy. Neuroimaging, including gadolinium-enhanced magnetic resonance imaging of the brain and spinal axis, identified diffuse leptomeningeal enhancement along the brainstem and spinal cord plus evidence of hemosiderosis. Pathologic and genetic analyses of biopsy material from enhancing intradural extramedullary tissue at the thoracolumbar junction was diagnostic of amyloidosis of a transthyretin type secondary to a TTR c.381T>G (p.Ile127Met) mutation. CONCLUSIONS OLMA represents a rare subtype of heritable transthyretin amyloidosis that may present with progressive neurological decline secondary to central nervous system leptomeningeal amyloid deposition. This case identifies the c.381T>G (p.Ile127Met) TTR mutation variant as being implicated in the OLMA phenotype.