Disorders of sex development (DSD) are congenital conditions with atypical development of chromosomal, gonadal, or anatomical sex. The estimated incidence ranges from 1 in 4,500–5,500 for strictly ...defined “ambiguous genitalia” to 1 in 300 or higher when a broader definition is implemented. In this study, we aim to define DSD phenotypes encountered in a large heterogeneous cohort of molecularly characterized Mendelian disorders in a single center. Data were retrieved for patients with documented abnormal genitalia based on the 2006 consensus criteria. Out of 149 patients (129 families) with compatible human phenotype ontology, 76 patients (68 families) had an identified genetic cause and were included in our analysis. Potentially causal variants were identified in 42 genes, and two patients had a dual molecular diagnosis. Six genes have no associated phenotype in OMIM (PIANP, CELSR2, USP2, FAM179B, TXNDC15, and CCDC96). Thirteen genes have non‐DSD OMIM phenotypes, thus we are expanding their phenotype to include DSD. We also highlight how certain disorders are under‐recognized despite their established DSD phenotype in OMIM, especially CTU2‐related DREAM‐PL syndrome and TSPYL1‐related sudden infant death with dysgenesis of the testes syndrome. In conclusion, this study of a large heterogeneous Mendelian cohort expands the list of genes and disorders beyond those classically DSD‐linked.
The human TRMT1 gene encodes an RNA methyltransferase enzyme responsible for catalyzing dimethylguanosine (m2,2G) formation in transfer RNAs (tRNAs). Frameshift mutations in TRMT1 have been shown to ...cause autosomal‐recessive intellectual disability (ID) in the human population but additional TRMT1 variants remain to be characterized. Here, we describe a homozygous TRMT1 missense variant in a patient displaying developmental delay, ID, and epilepsy. The missense variant changes an arginine residue to a cysteine (R323C) within the methyltransferase domain and is expected to perturb protein folding. Patient cells expressing TRMT1‐R323C exhibit a deficiency in m2,2G modifications within tRNAs, indicating that the mutation causes loss of function. Notably, the TRMT1 R323C mutant retains tRNA binding but is unable to rescue m2,2G formation in TRMT1‐deficient human cells. Our results identify a pathogenic point mutation in TRMT1 that perturbs tRNA modification activity and demonstrate that m2,2G modifications are disrupted in the cells of patients with TRMT1‐associated ID disorders.
The TRMT1 gene encodes a methyltransferase enzyme responsible for the formation of the dimethylguanosine modification in transfer RNA. Here, we present our biochemical and molecular characterization of a novel missense mutation in the human TRMT1 gene that causes intellectual disability disorder.
Infertility affects 10% of reproductive-age women and is extremely heterogeneous in etiology. The genetic contribution to female infertility is incompletely understood, and involves chromosomal and ...single-gene defects. Our aim in this study is to decipher single-gene causes in infertile women in whom endocrinological, anatomical, and chromosomal causes have been excluded. Our cohort comprises women with recurrent pregnancy loss and no offspring from spontaneous pregnancies (RPL,
n
= 61) and those who never achieved clinical pregnancy and were referred for in vitro fertilization primary infertility (PI),
n
= 14. Whole-exome sequencing revealed candidate variants in 14, which represents 43% of those with PI and 13% of those with RPL. These include variants in previously established female infertility-related genes (
TLE6
,
NLRP7
,
FSHR
, and
ZP1
) as well as genes with only tentative links in the literature (
NLRP5
). Candidate variants in genes linked to primary ciliary dyskinesia (
DNAH11
and
CCNO
) were identified in individuals with and without systemic features of the disease. We also identified variants in genes not previously linked to female infertility. These include one homozygous variant each in
CCDC68
,
CBX3
,
CENPH
,
PABPC1L
,
PIF1
,
PLK1
, and
REXO4
, which we propose as candidate genes for infertility based on their established biology or compatible animal models. Our study expands the contribution of single genes to the etiology of PI and RPL, improves the precision of disease classification at the molecular level, and offers the potential for future treatment and development of human genetics-inspired fertility regulators.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease that causes substantial morbidity. As is typical for many other multifactorial disorders, much of the heritability of SLE remains ...unknown. We identified a rare autosomal recessive form of SLE, in which autozygome analysis revealed a null mutation in the DNASE1L3 gene. The DNASE1L3-related SLE we describe was always pediatric in onset and correlated with a high frequency of lupus nephritis. Our findings confirm the critical role of impaired clearance of degraded DNA in SLE pathogenesis.
Arabs account for 5% of the world population and have a high burden of cardiometabolic disease, yet clinical utility of polygenic risk prediction in Arabs remains understudied. Among 5399 Arab ...patients, we optimize polygenic scores for 10 cardiometabolic traits, achieving a performance that is better than published scores and on par with performance in European-ancestry individuals. Odds ratio per standard deviation (OR per SD) for a type 2 diabetes score was 1.83 (95% CI 1.74-1.92), and each SD of body mass index (BMI) score was associated with 1.18 kg/m
difference in BMI. Polygenic scores associated with disease independent of conventional risk factors, and also associated with disease severity-OR per SD for coronary artery disease (CAD) was 1.78 (95% CI 1.66-1.90) for three-vessel CAD and 1.41 (95% CI 1.29-1.53) for one-vessel CAD. We propose a pragmatic framework leveraging public data as one way to advance equitable clinical implementation of polygenic scores in non-European populations.
Identifying genetic variants that lead to discernible phenotypes is the core of Mendelian genetics. An approach that considers embryonic lethality as a bona fide Mendelian phenotype has the potential ...to reveal novel genetic causes, which will further our understanding of early human development at a molecular level. Consanguineous families in which embryonic lethality segregates as a recessive Mendelian phenotype offer a unique opportunity for high throughput novel gene discovery as has been established for other recessive postnatal phenotypes.
We have studied 24 eligible families using autozygosity mapping and whole-exome sequencing. In addition to revealing mutations in genes previously linked to embryonic lethality in severe cases, our approach revealed seven novel candidate genes (THSD1, PIGC, UBN1, MYOM1, DNAH14, GALNT14, and FZD6). A founder mutation in one of these genes, THSD1, which has been linked to vascular permeability, accounted for embryonic lethality in three of the study families. Unlike the other six candidate genes, we were able to identify a second mutation in THSD1 in a family with a less severe phenotype consisting of hydrops fetalis and persistent postnatal edema, which provides further support for the proposed link between this gene and embryonic lethality.
Our study represents an important step towards the systematic analysis of "embryonic lethal genes" in humans.
Primary congenital glaucoma is a trabecular meshwork dysgenesis with resultant increased intraocular pressure and ocular damage.
CYP1B1
mutations remain the most common identifiable genetic cause. ...However, important questions about the penetrance of
CYP1B1
-related congenital glaucoma remain unanswered. Furthermore, mutations in other genes have been described although their exact contribution and potential genetic interaction, if any, with
CYP1B1
mutations are not fully explored. In this study, we employed modern genomic approaches to re-examine
CYP1B1
-related congenital glaucoma. A cohort of 193 patients (136 families) diagnosed with congenital glaucoma. We identified biallelic
CYP1B1
mutations in 80.8% (87.5 and 66.1% in familial and sporadic cases, respectively,
p
< 0.0086). The large family size of the study population allowed us to systematically examine penetrance of all identified alleles. With the exception of c.1103G>A (p.R368H), previously reported pathogenic mutations were highly penetrant (91.2%). We conclude from the very low penetrance and genetic epidemiological analyses that c.1103G>A (p.R368H) is unlikely to be a disease-causing recessive mutation in congenital glaucoma as previously reported. All cases that lacked biallelic
CYP1B1
mutations underwent whole exome sequencing. No mutations in
LTBP2
,
MYOC
or
TEK
were encountered. On the other hand, mutations were identified in genes linked to other ophthalmic phenotypes, some inclusive of glaucoma, highlighting conditions that might phenotypically overlap with primary congenital glaucoma (
SLC4A4
,
SLC4A11
,
CPAMD8
, and
KERA
). We also encountered candidate causal variants in genes not previously linked to human diseases:
BCO2
,
TULP2
, and
DGKQ
. Our results both expand and refine the genetic spectrum of congenital glaucoma with important clinical implications.
Clinical exome sequencing (CES) has greatly improved the diagnostic process for individuals with suspected genetic disorders. However, the majority remains undiagnosed after CES. Although ...understanding potential reasons for this limited sensitivity is critical for improving the delivery of clinical genomics, research in this area has been limited.
We first calculated the theoretical maximum sensitivity of CES by analyzing >100 families in whom a Mendelian phenotype is mapped to a single locus. We then tested the hypothesis that positional mapping can limit the search space and thereby facilitate variant interpretation by reanalyzing 33 families with "negative" CES and applying positional mapping.
We found that >95% of families who map to a single locus harbored genic (as opposed to intergenic) variants that are potentially identifiable by CES. Our reanalysis of "negative" CES revealed likely causal variants in the majority (88%). Several of these solved cases have undergone negative whole-genome sequencing.
The discrepancy between the theoretical maximum and the actual clinical sensitivity of CES is primarily in the variant filtration rather than the variant capture and sequencing phase. The solution to negative CES is not necessarily in expanding the coverage but rather in devising approaches that improve variant filtration. We suggest that positional mapping is one such approach.Genet Med advance online publication 06 October 2016.
Objective
Congenital hydrocephalus is an important birth defect, the genetics of which remains incompletely understood. To date, only 4 genes are known to cause Mendelian diseases in which congenital ...hydrocephalus is the main or sole clinical feature, 2 X‐linked (L1CAM and AP1S2) and 2 autosomal recessive (CCDC88C and MPDZ). In this study, we aimed to determine the genetic etiology of familial congenital hydrocephalus with the assumption that these cases represent Mendelian forms of the disease.
Methods
Exome sequencing combined, where applicable, with positional mapping.
Results
We identified a likely causal mutation in the majority of these families (21 of 27, 78%), spanning 16 genes, none of which is X‐linked. Ciliopathies and dystroglycanopathies were the most common etiologies of congenital hydrocephalus in our cohort (19% and 26%, respectively). In 1 family with 4 affected members, we identified a homozygous truncating variant in EML1, which we propose as a novel cause of congenital hydrocephalus in addition to its suggested role in cortical malformation. Similarly, we show that recessive mutations in WDR81, previously linked to cerebellar ataxia, mental retardation, and disequilibrium syndrome 2, cause severe congenital hydrocephalus. Furthermore, we confirm the previously reported candidacy of MPDZ by presenting a phenotypic spectrum of congenital hydrocephalus associated with 5 recessive alleles.
Interpretation
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
Discovery of genotype-phenotype relationships remains a major challenge in clinical medicine. Here, we combined three sources of phenotypic data to uncover a new mechanism for rare and common ...diseases resulting from collagen secretion deficits. Using a zebrafish genetic screen, we identified the ric1 gene as being essential for skeletal biology. Using a gene-based phenome-wide association study (PheWAS) in the EHR-linked BioVU biobank, we show that reduced genetically determined expression of RIC1 is associated with musculoskeletal and dental conditions. Whole-exome sequencing identified individuals homozygous-by-descent for a rare variant in RIC1 and, through a guided clinical re-evaluation, it was discovered that they share signs with the BioVU-associated phenome. We named this new Mendelian syndrome CATIFA (cleft lip, cataract, tooth abnormality, intellectual disability, facial dysmorphism, attention-deficit hyperactivity disorder) and revealed further disease mechanisms. This gene-based, PheWAS-guided approach can accelerate the discovery of clinically relevant disease phenome and associated biological mechanisms.
PDF
