Characterization of patients referred for non-specific intellectual disability testing: the importance of autosomal genes for diagnosis.

Genetic testing for non-specific intellectual disability (ID) presents challenges in daily clinical practice. Historically, the focus of the genetic elucidation of non-specific ID has been on genes on the X chromosome, and recent research has brought attention to the growing contribution of autosomal genes. In addition, next-generation sequencing (NGS) has greatly improved the ability to simultaneously analyze multiple genetic loci, making large panel testing a practical approach to testing for non-specific ID. We performed NGS analysis of a total of 90 genes implicated in non-specific ID. The 90 genes included 56 X-linked genes and 34 autosomal genes. Pathogenic variants were identified in 11 of 52 (21%) patient samples. Nine of the eleven cases harbored mutations in autosomal genes including AP4B1, STXB1, SYNGAP1, TCF4 and UBE3A. Our mutation-positive cases provide further evidence supporting the prevalence of autosomal mutations in patients referred for non-specific ID testing and the utility of their inclusion in multi-gene panel analysis.

The heritability of metabolic profiles in newborn twins.

Identifying genetic and metabolic biomarkers in neonates has the potential to improve diagnosis and treatment of common complex neonatal diseases, and potentially lead to risk assessment and preventative measures for common adulthood illnesses such as diabetes and cardiovascular disease. There is a wealth of information on using fatty acid, amino acid and organic acid metabolite profiles to identify rare inherited congenital diseases through newborn screening, but little is known about these metabolic profiles in the context of the 'healthy' newborn. Recent studies have implicated many of the amino acid and fatty acid metabolites utilized in newborn screening in common complex adult diseases such as cardiovascular disease, insulin resistance and obesity. To determine the heritability of metabolic profiles in newborns, we examined 381 twin pairs obtained from the Iowa Neonatal Metabolic Screening Program. Heritability was estimated using multilevel mixed-effects linear regression adjusting for gestational age, gender, weight and age at time of sample collection. The highest heritability was for short-chain acylcarnitines, specifically C4 (h²=0.66, P=2 × 10⁻¹6), C4-DC (h²=0.83, P<10⁻¹6) and C5 (h²=0.61, P=1 × 10⁻9). Thyroid stimulating hormone (h²=0.58, P=2 × 10⁻5) and immunoreactive trypsinogen (h²=0.52, P=3 × 10⁻9) also have a strong genetic component. This is direct evidence for a strong genetic contribution to the metabolic profile at birth and that newborn screening data can be utilized for studying the genetic regulation of many clinically relevant metabolites.

Microdeletions including YWHAE in the Miller-Dieker syndrome region on chromosome 17p13.3 result in facial dysmorphisms, growth restriction, and cognitive impairment.

BACKGROUND: Deletions in the 17p13.3 region are associated with abnormal neuronal migration. Point mutations or deletion copy number variants of the PAFAH1B1 gene in this genomic region cause lissencephaly, whereas extended deletions involving both PAFAH1B1 and YWHAE result in Miller-Dieker syndrome characterised by facial dysmorphisms and a more severe grade of lissencephaly. The phenotypic consequences of YWHAE deletion without deletion of PAFAH1B1 have not been studied systematically. METHODS: We performed a detailed clinical and molecular characterization of five patients with deletions involving YWHAE but not PAFAH1B1, two with deletion including PAFAH1B1 but not YWHAE, and one with deletion of YWHAE and mosaic for deletion of PAFAH1B1. RESULTS: Three deletions were terminal whereas five were interstitial. Patients with deletions including YWHAE but not PAFAH1B1 presented with significant growth restriction, cognitive impairment, shared craniofacial features, and variable structural abnormalities of the brain. Growth restriction was not observed in one patient with deletion of YWHAE and TUSC5, implying that other genes in the region may have a role in regulation of growth with CRK being the most likely candidate. Using array based comparative genomic hybridisation and long range polymerase chain reaction, we have delineated the breakpoints of these nonrecurrent deletions and show that the interstitial genomic rearrangements are likely generated by diverse mechanisms, including the recently described Fork Stalling and Template Switching (FoSTeS)/Microhomology Mediated Break Induced Replication (MMBIR). CONCLUSIONS: Microdeletions of chromosome 17p13.3 involving YWHAE present with growth restriction, craniofacial dysmorphisms, structural abnormalities of brain and cognitive impairment. The interstitial deletions are mediated by diverse molecular mechanisms.

Clinical and biochemical improvement of very long-chain acyl-CoA dehydrogenase deficiency in pregnancy.

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is an enzymatic defect of the fatty acid (FA) beta oxidation pathway. In catabolic states, such as labor and early postpartum period, patients are potentially prone to metabolic decompensation and subsequent rhabdomyolysis with increased risk for myoglobinuria and renal insufficiency. We report a 21-year-old primigravida with a previously characterized VLCAD deficiency, who experienced frequent and unprovoked episodes of rhabdomyolysis before pregnancy. As there was no published experience to guide her management, a detailed multidisciplinary care plan was established to minimize the potential morbidity. Although there is little known about the antenatal course of gravidae affected by VLCAD, we predicted that placental and fetal beta-oxidation in an unaffected pregnancy may temporize or even improve maternal FA beta-oxidation. Consistent with our prediction, we observed a significant clinical and biochemical improvement throughout her pregnancy, and she delivered vaginally with an uncomplicated postpartum course. We conclude that although VLCAD deficiency can present a therapeutic challenge during pregnancy, the beneficial placento-maternal metabolic interactions and the implementation of a proper peripartum management reassure a successful antenatal and perinatal outcome.