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Purpose Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM. Methods Clinical phenotyping, targeted or exome sequencing, and autozygome analysis. Results We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly —as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference—is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135 -related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2, YARS , FRMD4A , and THG1L , and proposing the candidacy of BPTF , MAP1B , CCNH , and PPFIBP1 . Conclusion Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.

Background: Cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ) is a heterogeneous group of genetic disorders that have been grouped by shared clinical features; all of these features are transmitted via an autosomal recessive mechanism. Four variants of this syndrome have been identified so far, and each one differs in terms of both clinical and genotypical features. CAMRQ4 is a rare genetic disorder characterized by mental retardation, ataxia or an inability to walk, dysarthria and, in some patients, quadrupedal gait. Methods: We investigated three Saudi families with CAMRQ4. Blood samples were collected from the affected patients, their parents, and healthy siblings. DNA was extracted from whole blood, and whole-exome sequencing was performed. Findings were confirmed by segregation analysis, which was performed on other family members. Results: Thus far, 17 patients have been affected by CAMRQ4. Genetic analysis of all patients, including our current patients, showed a mutation in the aminophospholipid transporter, class I, type 8A, member 2 gene (ATP8A2). A series of common phenotypical features have been reported in these patients, with few exceptions. Ataxia, mental retardation, and hypotonia were present in all patients, consanguinity in 90% and abnormal movements in 50%. Moreover, 40% achieved ambulation at least once in their lifetime, 40% had microcephaly, whereas 30% were mute. Magnetic resonance imaging (MRI) of the brain was normal in 60% of patients. Conclusions: We described the largest cohort of patients with CAMRQ4 syndrome and identified three novel mutations. CAMRQ4 syndrome should be suspected in patients presenting with ataxia, intellectual disability, hypotonia, microcephaly, choreoathetoid movements, ophthalmoplegia, and global developmental delay, even if brain MRI appears normal.

Purpose The application of genomic sequencing to investigate unexplained death during early human development, a form of lethality likely enriched for severe Mendelian disorders, has been limited. Methods In this study, we employed exome sequencing as a molecular autopsy tool in a cohort of 44 families with at least one death or lethal fetal malformation at any stage of in utero development. Where no DNA was available from the fetus, we performed molecular autopsy by proxy, i.e., through parental testing. Results Pathogenic or likely pathogenic variants were identified in 22 families (50%), and variants of unknown significance were identified in further 15 families (34%). These variants were in genes known to cause embryonic or perinatal lethality ( ALPL , GUSB , SLC17A5 , MRPS16 , THSD1 , PIEZO1 , and CTSA ), genes known to cause Mendelian phenotypes that do not typically include embryonic lethality ( INVS , FKTN , MYBPC3 , COL11A2 , KRIT1 , ASCC1 , NEB , LZTR1 , TTC21B , AGT , KLHL41 , GFPT1 , and WDR81 ) and genes with no established links to human disease that we propose as novel candidates supported by embryonic lethality of their orthologs or other lines of evidence ( MS4A7 , SERPINA11 , FCRL4 , MYBPHL , PRPF19 , VPS13D , KIAA1109 , MOCS3 , SVOPL , FEN1 , HSPB11 , KIF19 , and EXOC3L2 ). Conclusion Our results suggest that molecular autopsy in pregnancy losses is a practical and high-yield alternative to traditional autopsy, and an opportunity for bringing precision medicine to the clinical practice of perinatology.

Purpose Establishing links between Mendelian phenotypes and genes enables the proper interpretation of variants therein. Autozygome, a rich source of homozygous variants, has been successfully utilized for the high throughput identification of novel autosomal recessive disease genes. Here, we highlight the utility of the autozygome for the high throughput confirmation of previously published tentative links to diseases. Methods Autozygome and exome analysis of patients with suspected Mendelian phenotypes. All variants were classified according to the American College of Medical Genetics and Genomics guidelines. Results We highlight 30 published candidate genes ( ACTL6B , ADAM22 , AGTPBP1 , APC , C12orf4 , C3orf17 (NEPRO) , CENPF , CNPY3 , COL27A1 , DMBX1 , FUT8 , GOLGA2 , KIAA0556 , LENG8 , MCIDAS , MTMR9 , MYH11 , QRSL1 , RUBCN , SLC25A42 , SLC9A1 , TBXT , TFG , THUMPD1 , TRAF3IP2 , UFC1 , UFM1 , WDR81 , XRCC2 , ZAK ) in which we identified homozygous likely deleterious variants in patients with compatible phenotypes. We also identified homozygous likely deleterious variants in 18 published candidate genes ( ABCA2 , ARL6IP1 , ATP8A2 , CDK9 , CNKSR1 , DGAT1 , DMXL2 , GEMIN4 , HCN2 , HCRT , MYO9A , PARS2 , PLOD3 , PREPL , SCLT1 , STX3 , TXNRD2 , WIPI2 ) although the associated phenotypes are sufficiently different from the original reports that they represent phenotypic expansion or potentially distinct allelic disorders. Conclusions Our results should facilitate the timely relabeling of these candidate disease genes in relevant databases to improve the yield of clinical genomic sequencing.

Background Primordial dwarfism (PD) is a heterogeneous clinical entity characterised by severe prenatal and postnatal growth deficiency. Despite the recent wave of disease gene discovery, the causal mutations in many PD patients remain unknown. Objective To describe a PD family that maps to a novel locus. Methods Clinical, imaging and laboratory phenotyping of a new family with PD followed by autozygosity mapping, linkage analysis and candidate gene sequencing. Results We describe a multiplex consanguineous Saudi family in which two full siblings and one half-sibling presented with classical features of Seckel syndrome in addition to optic nerve hypoplasia. We were able to map the phenotype to a single novel locus on 4q25-q28.2, in which we identified a five base-pair deletion in PLK4, which encodes a master regulator of centriole duplication. Conclusions Our discovery further confirms the role of genes involved in centriole biology in the pathogenesis of PD.

Interleukin 12 receptor beta 1 (IL12Rβ1) deficiency is the most common cause of Mendelian susceptibility to mycobacterial disease (MSMD). MSMD usually predisposes the affected individuals to infections with weakly virulent mycobacteria such as Bacille Calmette-Guérin (BCG), environmental mycobacteria, non-typhoidal Salmonella, and certain other intracellular pathogens. MSMD usually presents with disseminated BCG infection after exposure to the BCG vaccine. Infections with non-typhoidal Salmonella are considered the second most common manifestation of MSMD; however, severe presentation with such organisms is unusual. In this report, we describe a case of a previously healthy infant who was found to have IL12Rβ1 deficiency after she presented with hemophagocytic lymphohistiocytosis (HLH) secondary to severe Salmonella enterica sepsis.This case report highlights the importance of considering the diagnosis of MSMD in any patient presenting with severe non-typhoidal Salmonella infections even in the absence of any exposure to low-virulent mycobacteria.

Leukocyte adhesion deficiency-III (LAD-III) is a rare recessive autosomal disorder characterized by bleeding syndrome of Glanzmann-type and life-threatening infections. The main etiology of this condition is variations in the gene, which encodes kindlin-3, an integrin-binding protein. This protein is responsible for the activation of fibrinogen receptors and integrin-mediated hematopoietic cell adhesion. So far, only limited cases of LAD-III have been reported. This case report discusses a two-year-old male infant from the Asir region, Saudi Arabia, who was referred to the pediatric hematology service due to recurrent ecchymosis and epistaxis. He was born at full term with a history of transient tachypnea of the newborn and recurrent bronchiolitis. The patient exhibited normal platelet count and coagulation profiles alongside a familial history of bleeding disorders, including a cousin with a similar condition. The patient also presented with hypospadias and café-au-lait spots. Laboratory findings revealed anemia, microcytosis, and hypochromia indicative of iron deficiency anemia. Whole exome sequencing (WES) identified a homozygous variant of uncertain significance in the gene, associated with autosomal recessive LAD-III. The patient was subsequently referred to an immunology subspecialty for further investigation and bone marrow transplant preparation. This case underscores the importance of comprehensive clinical and genetic evaluations in pediatric patients with unexplained bleeding tendencies.

Factor X (FX) deficiency is an extremely rare autosomal recessive inherited coagulation defect. We report a case of congenital Factor X-Riyadh deficiency discovered during a routine workup before a dental procedure. During routine work-up for dental surgery, prothrombin time (PT) and the international normalized ratio (INR) were prolonged. The prothrombin time (PT) was found to be 78.4 (normal 11-14 seconds) with an international normalized ratio (INR) of 7.83; the activated partial thromboplastin time (APTT) was 30.7 (normal 25-42 seconds). Specific coagulation factor assays confirmed an FX deficiency (<10 % of normal activity) and a mild factor VII deficiency 37% (normal 48%-124%). Molecular genetic analysis of the whole exome sequence (WES) confirmed the diagnosis of FX deficiency (homozygous pathogenic variant c. 271G>A p {Glu91Lys} chr13:113793685). The patient is currently on regular follow-up and is advised to take oral antifibrinolytic medications for any superficial or mucosal bleeding.

Variant nomenclature discrepancy was identified in the article.

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.