Our knowledge of disease genes in neurological disorders is incomplete. With the aim of closing this gap, we performed whole-exome sequencing on 143 multiplex consanguineous families in whom known disease genes had been excluded by autozygosity mapping and candidate gene analysis. This prescreening step led to the identification of 69 recessive genes not previously associated with disease, of which 33 are here described (SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, CLHC1, C12orf4, WDR93, ST7, MATN4, SEC24D, PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, KIAA1109, MTSS1L, XIRP1, KCTD3, CHAF1B, ARV1, ISCA2, PTRH2, GEMIN4, MYOCD, PDPR, DPH1, NUP107, TMEM92, EPB41L4A, and FAM120AOS). We also encountered instances in which the phenotype departed significantly from the established clinical presentation of a known disease gene. Overall, a likely causal mutation was identified in >73% of our cases. This study contributes to the global effort toward a full compendium of disease genes affecting brain function.

Primordial dwarfism (PD) is a disease in which severely impaired fetal growth persists throughout postnatal development and results in stunted adult size. The condition is highly heterogeneous clinically, but the use of certain phenotypic aspects such as head circumference and facial appearance has proven helpful in defining clinical subgroups. In this study, we present the results of clinical and genomic characterization of 16 new patients in whom a broad definition of PD was used (e.g., 3M syndrome was included). We report a novel PD syndrome with distinct facies in two unrelated patients, each with a different homozygous truncating mutation in CRIPT. Our analysis also reveals, in addition to mutations in known PD disease genes, the first instance of biallelic truncating BRCA2 mutation causing PD with normal bone marrow analysis. In addition, we have identified a novel locus for Seckel syndrome based on a consanguineous multiplex family and identified a homozygous truncating mutation in DNA2 as the likely cause. An additional novel PD disease candidate gene XRCC4 was identified by autozygome/exome analysis, and the knockout mouse phenotype is highly compatible with PD. Thus, we add a number of novel genes to the growing list of PD-linked genes, including one which we show to be linked to a novel PD syndrome with a distinct facial appearance. PD is extremely heterogeneous genetically and clinically, and genomic tools are often required to reach a molecular diagnosis.

Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy with multisystem involvement. So far, 18 BBS genes have been identified and the majority of them are essential for the function of BBSome, a protein complex involved in transporting membrane proteins into and from cilia. Yet defects in the identified genes cannot account for all the BBS cases. The genetic heterogeneity of this disease poses significant challenge to the identification of additional BBS genes. In this study, we coupled human genetics with functional validation in zebrafish and identified IFT27 as a novel BBS gene (BBS19). This is the first time an intraflagellar transport (IFT) gene is implicated in the pathogenesis of BBS, highlighting the genetic complexity of this disease.

BackgroundTo understand the contribution of Mendelian mutations to the burden of undiagnosed diseases that are suspected to be genetic in origin, we developed a next-generation sequencing-based multiplexing assay that encompasses the ~3000 known Mendelian genes. This assay, which we term the Mendeliome, comprises 13 gene panels based on clinical themes, covering the spectrum of pediatric and adult clinical genetic medicine. We explore how these panels compare with clinical whole exome sequencing (WES).ResultsWe tested 2357 patients referred with suspected genetic diagnoses from virtually every medical specialty. A likely causal mutation was identified in 1018 patients, with an overall clinical sensitivity of 43 %, comparing favorably with WES. Furthermore, the cost of clinical-grade WES is high (typically more than 4500 US dollars), whereas the cost of running a sample on one of our panels is around 75–150 US dollars, depending on the panel. Of the “negative” cases, 11 % were subsequently found by WES to harbor a likely causal mutation in a known disease gene (largely in genes identified after the design of our assay), as inferred from a representative sample of 178. Although our study population is enriched for consanguinity, 245 (24 %) of solved cases were autosomal dominant and 35 (4 %) were X-linked, suggesting that our assay is also applicable to outbred populations.ConclusionsDespite missing a significant number of cases, the current version of the Mendeliome assay can account for a large proportion of suspected genetic disorders, and provides significant practical advantages over clinical WES.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0693-2) contains supplementary material, which is available to authorized users.

Our study highlights the importance of recessive mutations in familial congenital hydrocephalus and expands the locus heterogeneity of this condition. Ann Neurol 2017;81:890-897.

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Meckel-Gruber syndrome (MKS, OMIM #249000) is a multiple congenital malformation syndrome that represents the severe end of the ciliopathy phenotypic spectrum. Despite the relatively common occurrence of this syndrome among Arabs, little is known about its genetic architecture in this population. This is a series of 18 Arab families with MKS, who were evaluated clinically and studied using autozygome-guided mutation analysis and exome sequencing. We show that autozygome-guided candidate gene analysis identified the underlying mutation in the majority (n ¼ 12, 71%). Exome sequencing revealed a likely pathogenic mutation in three novel candidate MKS disease genes. These include C5orf42, Ellis-van-Creveld disease gene EVC2 and SEC8 (also known as EXOC4), which encodes an exocyst protein with an established role in ciliogenesis. This is the largest and most comprehensive genomic study on MKS in Arabs and the results, in addition to revealing genetic and allelic heterogeneity, suggest that previously reported disease genes and the novel candidates uncovered by this study account for the overwhelming majority of MKS patients in our population.

Background - Childhood-onset cardiomyopathy (CMP) is a heterogenous group of conditions the etiology of which is largely unknown. The influence of consanguinity on the genetics of CMP has not been addressed at a large scale. Methods - To unravel the genetic etiology of childhood-onset CMP in a consanguineous population a categorized approach was adopted. Cases with childhood-onset CMP were consecutively recruited. Based on the likelihood of founder mutation and on the clinical diagnosis, genetic test was categorized to either: (i) Targeted Genetic Test (TGT) with: targeted mutation test, single gene test, or multi-gene panel for Noonan syndrome, or (ii) Untargeted genetic test with whole exome sequencing (WES) or whole genome sequencing (WGS). Several bioinformatics tools were used to filter the variants. Results - 205 unrelated probands with various forms of CMP were evaluated. The median age of presentation was 10 months. In 30.2% (n=62), TGT had a yield of 82.7% compared to 33.6% for WES/WGS (n=143) giving an overall yield of 53.7%. Strikingly, 96.4% of the variants were homozygous, 9% of which were found in 4 dominant genes. Homozygous variants were also detected in 7 novel candidates ( ACACB , AASDH , CASZ1 , FLII , RHBDF1 , RPL3L , ULK1 ). Conclusions - Our work demonstrates the impact of consanguinity on the genetics of childhood-onset CMP, the value of adopting a categorized population-sensitive genetic approach, and the opportunity of uncovering novel genes. Our data suggest that if a founder mutation is not suspected, adopting WES/WGS as a first-line test should be considered.