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Homozygosity-mapping approach was used to map the Cenani-Lenz syndrome (CLS) locus to chromosome 11p11.2-q13.1. The study results offer insight into the spectrum of congenital anomallies associated with abnormal lipoprotein receptor-dependent signaling.

A whole-genome oligonucleotide-based array comparative genomic hybridization (aCGH) method is used to identify a previously undescribed syndrome characterized by recurrent duplications of Xp11.22-p11.23 chromosomes associated with mental retardation, speech delay, and EEG anomalies in males and females. Research reveals that most of the rearrangements are mediated by recombinations between adjacent complex segmental duplications.

Abstract Background An increased risk of impaired intelligence (IQ) has been documented in valproate-exposed children, but investigations have not previously focused on those with a clinical diagnosis of Fetal Valproate Syndrome (FVS). Methods This cross sectional observational study recruited individuals with a diagnosis of FVS and completed standardized assessments of intellectual abilities making comparisons to a normative comparison group. Both mean difference (MD) and prevalence of scores below the lower average range were analyzed. Results The mean full-scale IQ in 31 individuals with FVS (mean age 14.97; range 6–27 years) was 19 points lower (19.55, 95% CI −24.94 to 14.15), and IQ scores <70 were present in 26%. The mean differences for verbal comprehension (21.07, 95% CI −25.84 to −16.29), working memory (19.77, 95% CI −25.00 to −14.55) and processing speed (16.87, 95% CI −22.24 to −11.50) performances were poorer than expected with the mean differences over one standard deviation from the comparison group. Sixty one percent of cases demonstrated disproportionately lower verbal comprehension ability. There were no significant group differences for IQ in high vs. moderate dose valproate or mono vs. polytherapy. There were no differences in IQ between those with and those without a major congenital malformation. The requirement for educational intervention was high at 74%. Conclusion Intellectual difficulties are a central feature of FVS and are more severe in their presentation in individuals with a diagnosis of valproate embryopathy. Individuals with FVS who present with the characteristic facial presentation should be considered at high risk of cognitive difficulties regardless of the dose of valproate exposure or the presence of a major congenital malformation. Highlights • Individuals with a diagnosis of fetal valproate syndrome demonstrated a higher frequency of intellectual or IQ difficulties. • Rates of IQ performance within the extremely low range were higher than those reported previously from non-clinical cohorts. • Verbal reasoning abilities were disproportionately impacted upon when compared to non-verbal reasoning. • Individuals without a major congenital malformation still demonstrated poorer intellectual ability. • Individuals with the valproate associated dysmorphic facial presentation should be reviewed by a neuropsychologist. [ABSTRACT FROM AUTHOR]

Introduction Oculo-auriculo-vertebral spectrum (OAVS OMIM 164210 ) is a craniofacial developmental disorder affecting the development of the structures derived from the 1st and the 2nd branchial arches during embryogenesis, with consequential maxillary, mandibular, and ear abnormalities. The phenotype in OAVS is variable and associated clinical features can involve the cardiac, renal, skeletal, and central nervous systems. Its aetiology is still poorly understood. Methods We have evaluated the clinical phenotypes of 51 previously unpublished patients with OAVS and their parents, and performed comparative genomic hybridization microarray studies to identify potential causative loci. Results Of all 51 patients, 16 (31%) had a family history of OAVS. Most had no relevant pre-natal history and only 5 (10%) cases had a history of environmental exposures that have previously been described as risk factors for OAVS. In 28 (55%) cases, the malformations were unilateral. When the involvement was bilateral, it was asymmetric. Ear abnormalities were present in 47 (92%) patients (unilateral in 24; and bilateral in 23). Hearing loss was common (85%), mostly conductive, but also sensorineural, or a combination of both. Hemifacial microsomia was present in 46 (90%) patients (17 also presented facial nerve palsy). Ocular anomalies were present in 15 (29%) patients. Vertebral anomalies were confirmed in 10 (20%) cases; 50% of those had additional heart, brain and/or other organ abnormalities. Brain abnormalities were present in 5 (10%) patients; developmental delay was more common among these patients. Limb abnormalities were found in 6 (12%) patients, and urogenital anomalies in 5 (10%). Array-CGH analysis identified 22q11 dosage anomalies in 10 out of 22 index cases screened. Discussion In this study we carried out in-depth phenotyping of OAVS in a large, multicentre cohort. Clinical characteristics are in line with those reported previously, however, we observed a higher incidence of hemifacial microsomia and lower incidence of ocular anomalies. Furthermore our data suggests that OAVS patients with vertebral anomalies or congenital heart defects have a higher frequency of additional brain, limb or other malformations. We had a higher rate of familial cases in our cohort in comparison with previous reports, possibly because these cases were referred preferentially to our genetic clinic where family members underwent examination. We propose that familial OAVS cases show phenotypic variability, hence, affected relatives might have been misclassified in previous reports. Moreover, in view of its phenotypic variability, OAVS is potentially a spectrum of conditions, which overlap with other conditions, such as mandibulofacial dysostosis. Array CGH in our cohort identified recurrent dosage anomalies on 22q11, which may contribute to, or increase the risk of OAVS. We hypothesize that although the 22q11 locus may harbour gene(s) or regulatory elements that play a role in the regulation of craniofacial symmetry and 1st and 2nd branchial arch development, OAVS is a heterogeneous condition and many cases have a multifactorial aetiology or are caused by mutations in as yet unidentified gene(s). [ABSTRACT FROM AUTHOR]

Abstract: We report a 4.5 Mb deletion of 2q33.1 in an individual with developmental delay and cleft palate. There have been various previous reports of deletions of 2q3, all with varying breakpoints and all larger than the current case. Whilst there is some variation in the phenotypes of patients with 2q3 deletions all share a commonly deleted region within 2q33.1 which includes SATB2, a gene previously shown to be associated with cleft palate. The phenotypic features of our patient are milder than those reported so far. [Copyright &y& Elsevier]

We report three probands from two unrelated consanguineous families of South Asian origin who all carry the same rare novel homozygous variant within the dead box helicase gene DDX59 in association with features of oral-facial-digital syndrome (OFDS). DDX59 variants have been reported previously in an unclassified, autosomal recessive form of OFDS; clinically associated with features including tongue lobulation, cleft palate, frontal bossing, hypertelorism and postaxial polydactyly. All three probands had lobulated tongues with tongue hamartomas, abnormal tongue tip, developmental delay and microcephaly, with just one proband demonstrating polydactlyly. The novel DDX59 variant was identified through autozygosity studies followed by sequencing of homozygous regions identified. It affects a stop codon, extending the protein product and is therefore predicted to be pathogenic. It is only the third reported DDX59 mutation associated with OFDS reported so far. [ABSTRACT FROM AUTHOR]

Purpose To assess the clinical usefulness of genetic testing in a pediatric population with inherited retinal disease (IRD). Design Single-center retrospective case series. Participants Eighty-five unrelated children with a diagnosis of isolated or syndromic IRD who were referred for clinical genetic testing between January 2014 and July 2016. Methods Participants underwent a detailed ophthalmic examination, accompanied by electrodiagnostic testing (EDT) and dysmorphologic assessment where appropriate. Ocular and extraocular features were recorded using Human Phenotype Ontology terms. Subsequently, multigene panel testing (105 or 177 IRD-associated genes) was performed in an accredited diagnostic laboratory, followed by clinical variant interpretation. Main Outcome Measures Diagnostic yield and clinical usefulness of genetic testing. Results Overall, 78.8% of patients (n = 67) received a probable molecular diagnosis; 7.5% (n = 5) of these had autosomal dominant disease, 25.4% (n = 17) had X-linked disease, and 67.2% (n = 45) had autosomal recessive disease. In a further 5.9% of patients (n = 5), a single heterozygous ABCA4 variant was identified; all these participants had a spectrum of clinical features consistent with ABCA4 retinopathy. Most participants (84.7%; n = 72) had undergone EDT and 81.9% (n = 59) of these patients received a probable molecular diagnosis. The genes most frequently mutated in the present cohort were CACNA1F and ABCA4 , accounting for 14.9% (n = 10) and 11.9% (n = 8) of diagnoses respectively. Notably, in many cases, genetic testing helped to distinguish stationary from progressive IRD subtypes and to establish a precise diagnosis in a timely fashion. Conclusions Multigene panel testing pointed to a molecular diagnosis in 84.7% of children with IRD. The diagnostic yield in the study population was significantly higher compared with that in previously reported unselected IRD cohorts. Approaches similar to the one described herein are expected to become a standard component of care in pediatric ophthalmology. We propose the introduction of genetic testing early in the diagnostic pathway in children with clinical and/or electrophysiologic findings, suggestive of IRD. [ABSTRACT FROM AUTHOR]

Summary: Background: Many women of childbearing potential take antiepileptic drugs, but the cognitive effects of fetal exposure are uncertain. We aimed to assess effects of commonly used antiepileptic drugs on cognitive outcomes in children up to 6 years of age. Methods: In this prospective, observational, assessor-masked, multicentre study, we enrolled pregnant women with epilepsy on antiepileptic drug monotherapy (carbamazepine, lamotrigine, phenytoin, or valproate) between October, 1999, and February, 2004, at 25 epilepsy centres in the UK and the USA. Our primary outcome was intelligence quotient (IQ) at 6 years of age (age-6 IQ) in all children, assessed with linear regression adjusted for maternal IQ, antiepileptic drug type, standardised dose, gestational birth age, and use of periconceptional folate. We also assessed multiple cognitive domains and compared findings with outcomes at younger ages. This study is registered with ClinicalTrials.gov, number NCT00021866. Findings: We included 305 mothers and 311 children (six twin pairs) in the primary analysis. 224 children completed 6 years of follow-up (6-year-completer sample). Multivariate analysis of all children showed that age-6 IQ was lower after exposure to valproate (mean 97, 95% CI 94–101) than to carbamazepine (105, 102–108; p=0·0015), lamotrigine (108, 105–110; p=0·0003), or phenytoin (108, 104–112; p=0·0006). Children exposed to valproate did poorly on measures of verbal and memory abilities compared with those exposed to the other antiepileptic drugs and on non-verbal and executive functions compared with lamotrigine (but not carbamazepine or phenytoin). High doses of valproate were negatively associated with IQ (r=–0·56, p<0·0001), verbal ability (r=–0·40, p=0·0045), non-verbal ability (r=–0·42, p=0·0028), memory (r=–0·30, p=0·0434), and executive function (r=–0·42, p=0·0004), but other antiepileptic drugs were not. Age-6 IQ correlated with IQs at younger ages, and IQ improved with age for infants exposed to any antiepileptic drug. Compared with a normative sample (173 [93%] of 187 children), right-handedness was less frequent in children in our study overall (185 [86%] of 215; p=0·0404) and in the lamotrigine (59 [83%] of 71; p=0·0287) and valproate (38 [79%] of 40; p=0·0089) groups. Verbal abilities were worse than non-verbal abilities in children in our study overall and in the lamotrigine and valproate groups. Mean IQs were higher in children exposed to periconceptional folate (108, 95% CI 106–111) than they were in unexposed children (101, 98–104; p=0·0009). Interpretation: Fetal valproate exposure has dose-dependent associations with reduced cognitive abilities across a range of domains at 6 years of age. Reduced right-handedness and verbal (vs non-verbal) abilities might be attributable to changes in cerebral lateralisation induced by exposure to antiepileptic drugs. The positive association of periconceptional folate with IQ is consistent with other recent studies. Funding: US National Institutes of Health, UK Epilepsy Research Foundation. [Copyright &y& Elsevier]

Abstract: Dravet syndrome has been found recently as an important underlying condition in cases of alleged vaccine encephalopathy after pertussis vaccination, where vaccination seemed to have precipitated the occurrence of the disease without modifying the long-term course. We report on a patient diagnosed with Angelman syndrome in her fifth decade, in whom the intellectual disability and epilepsy had been assumed to be caused by a vaccine encephalopathy following smallpox vaccination. Clinical features of Angelman syndrome had faded away. The history of the present patient suggests that genetic conditions other than Dravet syndrome can be associated with an alleged vaccine encephalopathy. A history of vaccine encephalopathy is rare among patients with learning disability and refractory epilepsy (1.4% in our cohort), but it should lead to consideration of a comprehensive genetic work-up if Dravet syndrome is excluded. The early history of the patient, when available, should guide the investigations. Medico-legal aspects are also discussed. [Copyright &y& Elsevier]

There are few cohort studies describing the adaptive functioning profile for Pitt-Hopkins syndrome (PTHS). In this study we examine the adaptive functioning profile for PTHS and compare it to Angelman syndrome (AS). Caregivers of 14 individuals with PTHS, 33 with deletion AS and 23 with non-deletion AS, completed the Vineland Adaptive Behavior Scales-II. The profile of adaptive functioning in PTHS was characterised by strengths in socialisation, followed by motor skills, communication then daily living skills. The PTHS group scored significantly lower than the non-deletion AS group on all domains except socialisation and significantly lower than the deletion AS group, for motor skills only. An uneven adaptive behavior profile for individuals with PTHS mirrors that of AS, with implications for assessment and intervention. [ABSTRACT FROM AUTHOR]

Abstract: Folate deficiency and the presence of the 677C>T (CT) polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene have been implicated in the causation of malformations in the fetus (particularly cleft lip and palate and neural tube defects). These birth defects are also recognised complications of exposure to antiepileptic drugs (AEDs). In pregnant women with epilepsy, the use of AEDs has an added effect on the physiological reduction in folate levels, which may be enhanced further by the presence of the 677C>T polymorphism in the mother. We studied the MTHFR genotype and rate of major malformations (MM) in 187 mother-child pairs where the mothers had epilepsy and in 236 matched control pairs. Sodium valproate (VPA) was the most commonly used drug and was associated with the highest rate of malformations (9.6%). 49% of mothers, both in the cases and controls were heterozygotes for the 677C>T polymorphism. The rate of MM was increased in offspring of mothers who were heterozygous or homozygous for 677C>T genotype amongst AED-exposed cases, but more so in those exposed to VPA. The effect of the VPA on the rate of MM was much higher [OR 7.79, 95% CI (1.45–41.9)] than the effect of the maternal 677C>T genotype [OR 2.57, 95% CI (0.28–23.7)]. There was no association between the child''s MTHFR genotype and the rate of MM. Conclusion: This study indicates that although the maternal MTHFR genotype may confer susceptibility to the teratogenic effect of AEDs, particularly VPA, it is likely that the main teratogenic effects are mediated through other mechanisms. [Copyright &y& Elsevier]

Abstract: X-linked mental retardation (XLMR) is a heterogeneous disorder with both syndromic and non-syndromic forms. Here we describe the clinical and molecular characterisation of a family with a syndromic form of XLMR with hypogonadism and short stature. We investigated a family in which four male members in two generations presented with hypergonadotrophic hypogonadism associated with development of small and abnormal testes. In two of the males, late-onset testicular ascent was noted. In addition, all affected males had short stature (<0.4th centile) and mild learning difficulties and three out of the four had microcephaly. Karyotypes were normal and endocrine investigations confirmed primary testicular failure. The phenotype segregated as an X-linked trait. Haplotype and genetic two-point linkage analysis with 22 microsatellites excluded the whole X chromosome except for a region on Xq25–Xq27 encompassing 13.7Mb with a maximum LOD score of 1.1 for marker DXS8038 at θ =0.05. One family previously described as having XLMR with hypogonadism and short stature maps to the same X chromosome region implicated in our family. However, the more severe mental retardation, muscle wasting and tremor described in this other family would suggest that our family is affected by a novel XLMR syndrome. [Copyright &y& Elsevier]

Ligase IV (LIG4) syndrome is a rare disorder of DNA damage repair caused by biallelic, pathogenic variants in LIG4. This is a phenotypically heterogeneous condition with clinical presentation varying from lymphoreticular malignancies in developmentally normal individuals to significant microcephaly, primordial dwarfism, radiation hypersensitivity, severe combined immunodeficiency and early mortality. Renal defects have only rarely been described as part of the ligase IV disease spectrum. We identified a consanguineous family where three siblings presenting with antenatal growth retardation, microcephaly, severe renal anomalies and skeletal abnormalities, including radial ray defects. Autozygosity mapping and exome sequencing identified a novel homozygous frameshift variant in LIG4, c.597_600delTCAG, p.(Gln200LysfsTer33), which segregated in the family. LIG4 is encoded by a single exon and so this frameshift variant is predicted to result in a protein truncated by 678 amino acids. This is the shortest predicted LIG4 protein product reported and correlates with the most severe clinical phenotype described to date. We note the clinical overlap with Fanconi anemia and suggest that LIG4 syndrome is considered in the differential diagnosis of this severe developmental disorder. [ABSTRACT FROM AUTHOR]

Melkersson Rosenthal syndromes (MRS) is a rare autosomal dominantly inherited neurocutaneous syndrome characterised by a triad of facial (seventh cranial) nerve palsy, recurrent orofacial swelling and fissuring of the tongue. A recent report implicated a heterozygous missense variant in SLC27A1 (FATP1) as the cause of this condition in members of an affected Chinese family. We undertook Sanger sequencing of this gene in 14 affected unrelated individuals affected by MRS. We did not detect any putative pathogenic variants. Our data indicates that there is both clinical and genetic heterogeneity in this condition and that the causative gene remains to be identified for the majority of cases. [ABSTRACT FROM AUTHOR]

Purpose To assess the utility of integrating genomic data from next-generation sequencing and phenotypic data to enhance the diagnosis of bilateral congenital cataract (CC). Design Evaluation of diagnostic technology. Participants Thirty-six individuals diagnosed with nonsyndromic or syndromic bilateral congenital cataract were selected for investigation through a single ophthalmic genetics clinic. Methods Participants underwent a detailed ophthalmic examination, accompanied by dysmorphology assessment where appropriate. Lenticular, ocular, and systemic phenotypes were recorded. Mutations were detected using a custom-designed target enrichment that permitted parallel analysis of 115 genes associated with CC by high-throughput, next-generation DNA sequencing (NGS). Thirty-six patients and a known positive control were tested. Suspected pathogenic variants were confirmed by bidirectional Sanger sequencing in relevant probands and other affected family members. Main Outcome Measures Molecular genetic results and details of clinical phenotypes were identified. Results Next-generation DNA sequencing technologies are able to determine the precise genetic cause of CC in 75% of individuals, and 85% patients with nonsyndromic CC were found to have likely pathogenic mutations, all of which occurred in highly conserved domains known to be vital for normal protein function. The pick-up rate in patients with syndromic CC also was high, with 63% having potential disease-causing mutations. Conclusions This analysis demonstrates the clinical utility of this test, providing examples where it altered clinical management, directed care pathways, and enabled more accurate genetic counseling. This comprehensive screen will extend access to genetic testing and lead to improved diagnostic and management outcomes through a stratified medicine approach. Establishing more robust genotype–phenotype correlations will advance knowledge of cataract-forming mechanisms. [ABSTRACT FROM AUTHOR]