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.

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This is a report of a female newborn baby who presented at the age of one hour after birth with signs of respiratory distress with marked cyanosis. The critical condition of the baby and the stormy course of the disorder highlighted the importance of starting immediate management and establishing an etiological diagnosis, as this will make the difference in the outcome and the prognosis. Clinical presentationThis was a female infant born at term after an uneventful pregnancy. Antenatal ultrasound did not show fetal anomaly and antenatal serology for infectious diseases was not significant. High vaginal swab from the mother was negative for group B streptococcus. Delivery was by elective Caesarean section because of previous section. Apgar Score was 9 and 10 at 1 and 5 minutes respectively. Birth weight was 2230 grams but the baby was vigorous with an oxygen saturation of 95% in room air at 15 minutes and was eventually sent to the normal newborn nursery.At the age of one hour the pediatric doctor was called because the baby was showing signs of respiratory distress with marked cyanosis and an oxygen saturation ranging from 70% to 80% in room air. Clinical examination revealed no signs of dysmorphism but the baby was showing respiratory distress with marked cyanosis. There were no abnormal findings on examination of the cardiovascular system. On admission to the neonatal intensive care unit (NICU) the baby was started on nasal continuous positive airway pressure (nCPAP) of 6 cm H 2 O, FiO 2 of 0.3 but the oxygen saturation (SaO 2 ) remained unchanged at 80% and below. Blood gases at that time showed a pH of 7.12, pCO 2 of 45 mm Hg and a bicarbonate of 14 mmol/I with a base deficit of -13. With the increasing requirements of oxygen the baby was shifted from nCPAP to mechanical ventilation. In spite of reaching an inspiratory pressure of 26 cm H 2 O the baby remained hypoxemic at which point a diagnosis of persistent pulmonary hypertension (PPHN) was entertained and high frequency oscillatory ventilation (HFOV) was started together with inhaled nitric oxide. Soon after admission the baby was noticed to have systemic hypotension requiring inotropic therapy. Dopamine and dobutamine were titrated to a maximum of 20 micrograms per kilogram per minute after which epinephrine and hydrocortisone were instituted consecutively because of persistent hypotension. At this point the differential diagnosis rested between cyanotic congenital heart disease, septic shock or metabolic disorder and antibiotics were started.On interviewing the family it was revealed that the parents were first-degree cousins with five living children but one of the siblings who was a male infant expired at the age of two days and the death was attributed to possible hypoxic ischemic encephalopathy, septic shock or a metabolic disorder most likely adrenal insufficiency.Taking into account the clinical presentation and the family history the baby was investigated accordingly. A chest radiograph revealed normal lung fields with no cardiomegaly. I...

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