Marwan Shinawi

Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response

Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response.

Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster.

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.

Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities

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 defects, developmental delay, schizophrenia and related psychoses. 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 microdeletion and microduplication, respectively. Notably, a paralog of the HYDIN gene located on 16q22.2 and implicated in autosomal recessive hydrocephalus was inserted into the 1q21.1 region during the evolution of Homo sapiens; 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.

A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome)

Purpose: To evaluate the safety and efficacy of recombinant human iduronate-2-sulfatase (idursulfase) in the treatment of mucopolysaccharidosis II.Methods: Ninety-six mucopolysaccharidosis II patients between 5 and 31 years of age were enrolled in a double-blind, placebo-controlled trial. Patients were randomized to placebo infusions, weekly idursulfase (0.5 mg/kg) infusions or every-other-week infusions of idursulfase (0.5 mg/kg). Efficacy was evaluated using a composite endpoint consisting of distance walked in 6 minutes and the percentage of predicted forced vital capacity based on the sum of the ranks of change from baseline.Results: Patients in the weekly and every-other-week idursulfase groups exhibited significant improvement in the composite endpoint compared to placebo (P = 0.0049 for weekly and P = 0.0416 for every-other-week) after one year. The weekly dosing group experienced a 37-m increase in the 6-minute-walk distance (P = 0.013), a 2.7% increase in percentage of predicted forced vital capacity (P = 0.065), and a 160 mL increase in absolute forced vital capacity (P = 0.001) compared to placebo group at 53 weeks. Idursulfase was generally well tolerated, but infusion reactions did occur. Idursulfase antibodies were detected in 46.9% of patients during the study.Conclusion: This study supports the use of weekly infusions of idursulfase in the treatment of mucopolysaccharidosis II.

Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size

Background Deletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay. Method We indentified 27 deletions and 18 duplications of 16p11.2 were identified in 0.6% of all samples submitted for clinical array-CGH (comparative genomic hybridisation) analysis. Detailed molecular and phenotypic characterisations were performed on 17 deletion subjects and ten subjects with the duplication. Results The most common clinical manifestations in 17 deletion and 10 duplication subjects were speech/language delay and cognitive impairment. Other phenotypes in the deletion patients included motor delay (50%), seizures (∼40%), behavioural problems (∼40%), congenital anomalies (∼30%), and autism (∼20%). The phenotypes among duplication patients included motor delay (6/10), behavioural problems (especially attention deficit hyperactivity disorder (ADHD)) (6/10), congenital anomalies (5/10), and seizures (3/10). Patients with the 16p11.2 deletion had statistically significant macrocephaly (p<0.0017) and 6 of the 10 patients with the duplication had microcephaly. One subject with the deletion was asymptomatic and another with the duplication had a normal cognitive and behavioural phenotype. Genomic analyses revealed additional complexity to the 16p11.2 region with mechanistic implications. The chromosomal rearrangement was de novo in all but 2 of the 10 deletion cases in which parental studies were available. Additionally, 2 de novo cases were apparently mosaic for the deletion in the analysed blood sample. Three de novo and 2 inherited cases were observed in the 5 of 10 duplication patients where data were available. Conclusions Recurrent reciprocal 16p11.2 deletion and duplication are characterised by a spectrum of primarily neurocognitive phenotypes that are subject to incomplete penetrance and variable expressivity. The autism and macrocephaly observed with deletion and ADHD and microcephaly seen in duplication patients support a diametric model of autism spectrum and psychotic spectrum behavioural phenotypes in genomic sister disorders.

Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders

Background: Microdeletions within chromosome 15q13.3 are associated both with a recently recognised syndrome of mental retardation, seizures, and dysmorphic features, and with schizophrenia. Methods and results: Based on routine diagnostic testing of ∼8200 samples using array comparative genomic hybridisation, we identified 20 individuals (14 children and six parents in 12 families) with microdeletions of 15q13.3. Phenotypes in the children included developmental delay, mental retardation, or borderline IQ in most and autistic spectrum disorder (6/14), speech delay, aggressiveness, attention deficit hyperactivity disorder, and other behavioural problems. Both parents were available in seven families, and the deletion was de novo in one, inherited from an apparently normal parent in four, and inherited from a parent with learning disability and bipolar disorder in two families. Of the 14 children, six in five families were adopted, and DNA was available for only one of these 10 biological parents; the deletion was very likely inherited for one of these families with two affected children. Among the unavailable parents, two mothers were described as having mental retardation, another mother as having “mental illness”, and one father as having schizophrenia. We hypothesise that some of the unavailable parents have the deletion. Conclusions: The occurrence of increased adoption, frequent autism, bipolar disorder, and lack of penetrance are noteworthy findings in individuals with deletion 15q13.3. A high rate of adoption may be related to the presence of the deletion in biological parents. Unconfirmed histories of antisocial behaviours in unavailable biological parents raise the concern that future research may show that deletion 15q13.3 is associated with such behaviours.

The array CGH and its clinical applications

Array comparative genomic hybridization (aCGH) is a technique enabling high-resolution, genome-wide screening of segmental genomic copy number variations (CNVs). It is becoming an essential and a routine clinical diagnostic tool and is gradually replacing cytogenetic methods. Most of the clinically available aCGH platforms are designed to detect aneuploidies, well-characterized microdeletion/microduplication syndromes and subtelomeric or other unbalanced chromosomal rearrangements. In addition, aCGH can uncover numerous CNVs of unclear significance scattered throughout the human genome. But this technology is not able to identify balanced chromosomal imbalances such as translocations and inversions and some ploidies. aCGH increased the ability to detect segmental genomic CNVs in patients with global developmental delay, mental retardation, autism, multiple congenital anomalies and dysmorphism, and is becoming a powerful tool in disease gene discovery and prenatal diagnostics. This tool is also showing promising data in cancer research and in the diagnosis, classification and prognostication of different malignancies.

A small recurrent deletion within 15q13.3 is associated with a range of neurodevelopmental phenotypes.

We report a recurrent 680-kb deletion within chromosome 15q13.3 in ten individuals, from four unrelated families, with neurodevelopmental phenotypes including developmental delay, mental retardation and seizures. This deletion likely resulted from nonallelic homologous recombination between low-copy repeats on the normal and inverted region of chromosome 15q13.3. Although this deletion also affects OTUD7A, accumulated data suggest that haploinsufficiency of CHRNA7 is causative for the majority of neurodevelopmental phenotypes in the 15q13.3 microdeletion syndrome.

Familial Mediterranean fever : prevalence, penetrance and genetic drift

FMF is widely distributed in populations inhabiting the Mediterranean basin. It is mainly attributed to five founder mutations (M680I, M694V, M694I, V726A, E148Q) in the MEFV gene. The frequencies and distribution of these mutations in 146 FMF patients, of Arab and Jewish descent, were compared to that observed in 1173 healthy individuals of pertinent ethnic groups. Five mutations accounted for 91% of FMF chromosomes in our patients. Mutation M694V, predominant in North African Jews, was observed in all patients other than Ashkenazi Jews; mutation V726A was prevalent among all patients other than North African Jews; mutations M694I and M680I were mainly confined to Arab patients. Overall carrier rates, for four mutations (M680I, M694V, V726A, E148Q), were extremely high in our healthy cohort composed of Ashkenazi (n=407); Moroccan (n=243); Iraqi Jews (n=205); and Muslim Arabs (n=318); calculated at 1 : 4.5; 1 : 4.7; 1 : 3.5 and 1 : 4.3 respectively. The V726A allele prevalent among Ashkenazi and Iraqi Jews and Muslim Arabs (carrier rates: 7.4, 12.8 and 7.3%, respectively) was not found among Moroccan Jews. The M694V allele detected among Moroccan and Iraqi Jews and Muslim Arabs (carrier rates 11.1, 2.9 and 0.6%, respectively) was not observed among Ashkenazim. The overall frequency of mutations V726A and E148Q in Ashkenazim, Iraqi Jews and Arabs indicates that the bulk of individuals that comply with the genetic definition of FMF remain asymptomatic.

Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome

Purpose: This study evaluated the safety and effectiveness of long-term enzyme replacement therapy with idursulfase (recombinant human iduronate-2-sulfatase) in patients with Hunter syndrome.Methods: All 94 patients who completed a 53-week double-blinded study of idursulfase enrolled in this open-labeled extension study and received intravenous idursulfase at a dose of 0.5 mg/kg weekly for 2 years, and clinical outcomes and safety were assessed.Results: No change in percent predicted forced vital capacity was seen, but absolute forced vital capacity demonstrated sustained improvement and was increased 25.1% at the end of the study. Statistically significant increases in 6-minute walking test distance were observed at most time points. Mean liver and spleen volumes remained reduced throughout the 2-year extension study. Mean joint range of motion improved for the shoulder and remained stable in other joints. Both the parent- and child-assessed Child Health Assessment Questionnaire Disability Index Score demonstrated significant improvement. Infusion-related adverse events occurred in 53% of patients and peaked at Month 3 of treatment and declined thereafter. Neutralizing IgG antibodies were detected in 23% of patients and seemed to attenuate the improvement in pulmonary function.Conclusions: Weekly infusions of idursulfase result in sustained clinical improvement during 3 years of treatment.