In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016–December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving ITPR1, VAMP1, MCTP2, and TBP). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes (ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1, and WHSC1) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease (AKAP6 in intellectual disability and UBR4 in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most “negative” clinical exome tests are unsolved due to interpretation rather than technical limitations.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-017-1821-8) contains supplementary material, which is available to authorized users.

BackgroundThere is lack of data on prevalence of celiac disease (CD) in children with type 1 diabetes (T1D) in Arabs in the Middle East. The present investigation aims to study the prevalence rate and clinical characteristics of CD among Saudi children with T1D using a combination of the most sensitive and specific screening serologic tests (anti- tissue transglutaminase antibodies IgA [anti-TTG] and ednomyseal antibodies [EMA]) and to determine the lower cut-off value of anti- anti-TTG level that best predicts CD in children with T1D.MethodsChildren with T1D following in diabetic clinic have been prospectively screened for presence of CD, over a two-year period (2008–2010), by doing anti-TTG, EMA, and total IgA. Children with positive anti-TTG titres (>50 U/ml) and/or EMA and children with persistently low positive anti-TTG titres (two readings 20–50 U/ml; within 6 months intervals) had upper endoscopy and 6 duodenal biopsies.ResultsOne hundred and six children with T1D have been screened for CD: age ranged between 8 months to 15.5 years (62 females). Nineteen children had positive anti-TTG and/or EMA, however only 12 children had biopsy proven CD (11.3%). Five of 12 had gastrointestinal symptoms (42%). Children with T1D and CD had significantly lower serum iron than children with T1D alone (8.5 μgm/L Vs 12.5 μgm/L; P = 0.014). The sensitivity and specificity of anti-TTG were 91.6% and 93.6%, with a positive and negative predictive value of 64.7% and 98.8%, respectively. Receiver operated characteristics analysis for the best cut-off value of anti-TTG level for diagnosis of CD was 63 units (sensitivity 100% and specificity 98.8%).ConclusionCD is highly prevalent among Saudi children with T1D. Anti-TTG titres more than 3 times the upper limit of normal has very high sensitivity and specificity for diagnosis of CD in T1D children.

BackgroundThe Prevalence of liver disease among diabetics has been estimated to be between 17% and 100%. Most of these data were obtained from adult studies. The aim of our study was to screen for liver disease among type 1 diabetic children.MethodsChildren with type 1 diabetes following in clinic have been examined for existence of liver disease, from November 2008 to November 2009. All were subjected to the following: History, physical examination, liver function tests, fasting lipid profile, HbA1C, and ultrasound of the liver. A hyperechogenic liver and/or hepatomegaly on ultrasound were attributed most likely to excess glycogen or fat in the liver, after negative extensive work-up to rule out other underlying liver disease.Results106 children with type 1 diabetes were studied: age ranged between 8 months to 15.5 years, sixty two patients were females. Twenty two patients (21%) were identified to have abnormal findings on ultrasound of the liver: 10 patients had hepatomegaly and 12 had hyperechogenic liver. The group with hyperechogenic liver had poorer glycemic control than patients with normal liver (Mean HbA1c 12.14% Vs 10.7%; P value = 0.09). Hyperechogenic liver resolved in 60% at 6 months follow-up upon achieving better glycemic control.ConclusionsHyperechogenic liver and/or hepatomegaly are not uncommon in children with type 1 diabetes and tend to be more prevalent among children with poor glycemic control. Type 1 diabetes related hepatopathy is reversible by optimizing glycemic control. Because of its safety, and reliability, ultrasound can be used to screen for hepatopathy in type 1 diabetic child.

BackgroundNeuropsychiatric disorders are common forms of disability in humans. Despite recent progress in deciphering the genetics of these disorders, their phenotypic complexity continues to be a major challenge. Mendelian neuropsychiatric disorders are rare but their study has the potential to unravel novel mechanisms that are relevant to their complex counterparts.ResultsIn an extended consanguineous family, we identified a novel neuropsychiatric phenotype characterized by severe speech impairment, variable expressivity of attention deficit hyperactivity disorder (ADHD), and motor delay. We identified the disease locus through linkage analysis on 15q21.2, and exome sequencing revealed a novel missense variant in GNB5. GNB5 encodes an atypical β subunit of the heterotrimeric GTP-binding proteins (Gβ5). Gβ5 is enriched in the central nervous system where it forms constitutive complexes with members of the regulator of G protein signaling family of proteins to modulate neurotransmitter signaling that affects a number of neurobehavioral outcomes. Here, we show that the S81L mutant form of Gβ5 has significantly impaired activity in terminating responses that are elicited by dopamine.ConclusionsWe demonstrate that these deficits originate from the impaired expression of the mutant Gβ5 protein, resulting in the decreased ability to stabilize regulator of G protein signaling complexes. Our data suggest that this novel neuropsychiatric phenotype is the human equivalent of Gnb5 deficiency in mice, which manifest motor deficits and hyperactivity, and highlight a critical role of Gβ5 in normal behavior as well as language and motor development in humans.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1061-6) contains supplementary material, which is available to authorized users.

Background: Appropriate asthma management in children reduces emergency department visits, hospitalization, and improves the quality of life. We aim to assess the level of children asthma control and its association with parental knowledge. Methods: A prospective study conducted to measure childhood asthma control with a validated childhood asthma control test (C-ACT), and to assess asthma knowledge among the parents of children aged 4-11 years and their parents upon asthma clinic visits. C-ACT score ≤ 19 is considered as uncontrolled child asthma. Results: We have invited 238 parents to participate in the study; 177 (74.4%) completed the survey. The mean age of the parents and their children were 38.8 ± 7.6 and 7.8 ± 2.7 years, respectively; 28.2% of parents were smokers, and 46.3% of them were college graduated. Nearly 61.6% of the parents and children scored ≤ 19 on C-ACT; 54.2% and 37.9% of parents knew how inhaled salbutamol and corticosteroids work, respectively. A quarter of the parents received an asthma action plan. Multinomial logistic regression analysis showed that parents who did not know their children's medications name (OR, 6.1; 95% CI, 2.15-17.29), and when to use inhaled corticosteroid (OR, 2.1; 95% CI, 1.32-3.45) were independent factors predicting uncontrolled asthma in children with score ≤ 19. Conclusions: The study indicated that there is an association between poor asthma control (scored ≤ 19 on C-ACT) and parental knowledge of asthma medications. The parents should be educated thoroughly on asthma care, including medications used to minimize asthma exacerbations in their children. K E Y W O R D S bronchial diseases, lung diseases, pediatric asthma 1 | INTRODUCTION Asthma is a common chronic respiratory disease in children. Uncontrolled asthma increases mortality, morbidity, emergency department (ED) visits, hospitalization, reduces the quality of life as well as increases health care costs. 1 An overall prevalence of asthma in children from Saudi Arabia ranged from 8% to 25%, depending on studies conducted over the past three decades. A recent study in Saudi Arabia reported prevalence of 45% of uncontrolled asthma in children. 2,3 In western countries, the reported prevalence of asthma in children was 8.6% in the United States (uncontrolled asthma 46%, 2010), and 11% in France (uncontrolled asthma 37.6%, 2013). 4-7