Results: Of 20 newborns studied, 8 received a diagnosis on the basis of next-generation sequencing (diagnostic rate 40%). The diagnoses were renal tubular dysgenesis, SCN1A-related encephalopathy syndrome, myotubular myo pathy, FTO deficiency syndrome, cranioectodermal dysplasia, congenital myasthenic syndrome, autosomal dominant intellectual disability syndrome type 7 and Denys-Drash syndrome.Interpretation: This pilot study highlighted the potential of next-generation sequencing to deliver molecular diagnoses rapidly with a high success rate. With broader use, this approach has the potential to alter health care delivery in the NICU. AbstractSee also www.cmaj.ca/lookup/doi/10.1503/cmaj.160490Research CMAJ, August 9, 2016, 188(11) E255and clinicians providing care. 7 The inability to arrive at a timely and efficient diagnosis repre sents a substantial lost opportunity, as a diagno sis can limit or even halt further invasive, and at times futile, investigations for the neonate. Importantly, an accurate diagnosis informs prog nosis and may guide management decisions.The advent of nextgeneration sequencing has greatly advanced the ability to rapidly identify the novel genes responsible for disease. 8 Whole exome sequencing (sequencing of the coding portion of the genome) is beginning to be used on a clinical basis in tertiary care centres.9,10 In these initial clinical cohort studies, a molecular diagnosis was provided by wholeexome sequencing for about 25% of families. The pro portion increased to 31% when the patient's par ents were also analyzed. 9 Another study used retro spective wholegenome sequencing to make a diagnosis in 57% of 35 children from the inten sive care setting. 11Although wholeexome and wholegenome sequencing are powerful tools, important condi tions are required for translation of these meth ods to the clinic or hospital setting. The avail ability of highthroughput sequencers, complex and costly infrastructure, and personnel with bioinformatics expertise are prerequisites. These resources may not be broadly available within some health care systems, and other strategies may be more relevant and effective.Another attractive alternative is analysis based on nextgeneration sequencing that focuses only on the clinically relevant genes with known associated clinical phenotypes. 12This strategy offers several advantages over wholeexome or wholegenome sequencinginterpretation of variants may be more straight forward, a higher depth of coverage can be read ily achieved, and less infrastructure and fewer personnel are required -all of which contribute to a more rapid return of results.For this pilot study, we evaluated the perform ance of a targeted nextgeneration sequencing panel that included 4813 "diseaserelevant" genes in a cohort of newborns with rare disease in the NICU and assessed the effectiveness of this method to accurately diagnose these critically ill babies. Methods ParticipantsWe recruited patients for this pilot study between January and December 2014 from the NICUs of 2 regional hospi...

Our findings are consistent with previous reports that homozygous mutations in FTO can lead to rare growth retardation and developmental delay syndrome, and further support the proposal that FTO plays an important role in early development of human central nervous and cardiovascular systems.

BackgroundChromosomal deletions encompassing DYRK1A have been associated with intellectual disability for several years. More recently, point mutations in DYRK1A have been shown to be responsible for a recognizable syndrome characterized by microcephaly, developmental delay and intellectual disability (ID) as well as characteristic facial features. Here we present 2 individuals with novel mutations in DYRK1A, and a review of the cases reported to date.Case presentationBoth individuals presented with the well-known characteristic features, as well as rarer anomalies seen in a minority of patients. Patient 1 presented shortly after birth with an enlarged cisterna magna, distal contractures, and distinctive facies that included bitemporal narrowing and deep set eyes. A de novo splice site mutation in DYRK1A [c.951 + 4_951 + 7delAGTA; p.Val222Aspfs*22] was identified by next generation sequencing. Patient 2 presented at 7 months of age with microcephaly and dysmorphic features. She went several years without a diagnosis until a de novo DYRK1A nonsense mutation [c.787C>T; p.(Arg263*)] was identified at age 12. These individuals, and the 52 cases reviewed from the literature, show the characteristic features of the DYRK1A-related syndrome including global developmental delay, ID, microcephaly, feeding difficulties, and the facial gestalt. Other common findings include seizures, vision defects, brain abnormalities and skeletal abnormalities of the hands and feet. Less common features include optic nerve defects, contractures, ataxia, and cardiac anomalies.ConclusionDYRK1A testing should be considered in individuals with the facial features, intellectual disability and post-natal microcephaly. Once diagnosed with DYRK1A-related intellectual disability, a cardiac and ophthalmologic assessment would be recommended as would routine surveillance by a pediatrician for psychomotor development, growth, and feeding.

Objective To identify pre or post processing semen analysis parameters that may be predictive of successful pregnancy in couples with male factor infertility undergoing intra uterine insemination (IUI). To evaluate the pregnancy rate based on ovulation inducing agent in couples with male factor infertility per the 2010 world health organization criteria treated with IUI. Study Design This retrospective study was performed at Stanford University medical center. All couples with male factor infertility fitting inclusion criteria were included over a 2 year period of time. 147 couples with male factor infertility were included and 356 IUIs were analyzed. All subjects in this study had Kruger strict analysis >4% normal forms. Logistic regression analysis was used to control for confounding effects and multiplicity. Results The overall pregnancy rate was 5.3%. No parameter in either the pre or post analysis predicted pregnancy. Furthermore, it was found that natural cycle and letrazole treatment had similar pregnancy rates (3% and 3%) p=ns. Similar outcomes were also observed between clomiphene citrate and gonadotropin stimulated cycles (7.5% and 6.0%) p=ns. Conclusions Total motile sperm count which has been found to be a predictor of pregnancy when evaluated in isolation, may be due to a confounding effect. These low pregnancy rates should be considered when deciding whether to suggest IUI and when selecting a protocol for ovulation induction for couples with male factor infertility.