Array comparative genomic hybridization (array CGH) has revolutionized the cytogenetic testing available for patients with learning disabilities who have “chromosomal” phenotypes with dysmorphic ...features and multiple anomalies. Screening large patient cohorts with mental retardation by array CGH has recently lead to the characterization of many novel microdeletion and microduplication syndromes, initially according to the shared cytogenetic aberrations, with secondary characterization of the corresponding phenotypes. This review provides a detailed clinical and molecular cytogenetic description of several of the most common of these aberrations. We have chosen to focus on patients in whom the cytogenetic abnormalities were principally described by array CGH, rather than by G-banded karyotyping or fluorescence in-situ hybridization. The syndromes that we have chosen include the 17q21.31 deletion and 17q21.31 duplication syndromes, 15q13.3 deletion syndrome, 16p11.2 deletion syndrome, 15q24 deletion syndrome, 1q41q42 deletion syndrome, 2p15p16.1 deletion syndrome and 9q22.3 deletion syndrome. In time, we hypothesize that at least some of these will become as clinically well characterized and recognizable to the clinician as the commoner microdeletion syndromes today. Although the full extent of the phenotypes is still evolving for many of these novel microdeletions, it is clear that array CGH has heralded an unparalleled era of discovery for clinical cytogenetics.
Anophthalmia and microphthalmia (A/M) are significant eye defects because they can have profound effects on visual acuity. A/M is associated with non-ocular abnormalities in an estimated 33–95% of ...cases and around 25% of patients have an underlying genetic syndrome that is diagnosable. Syndrome recognition is important for targeted molecular genetic testing, prognosis and for counseling regarding recurrence risks. This review provides clinical and molecular information for several of the commonest syndromes associated with A/M: Anophthalmia–Esophageal–Genital syndrome, caused by SOX2 mutations, Anophthalmia and pituitary abnormalities caused by OTX2 mutations, Matthew-Wood syndrome caused by STRA6 mutations, oculofaciocardiodental syndrome and Lenz microphthalmia caused by BCOR mutations, Microphthalmia Linear Skin pigmentation syndrome caused by HCCS mutations, Anophthalmia, pituitary abnormalities, polysyndactyly caused by BMP4 mutations and Waardenburg anophthalmia caused by mutations in SMOC1. In addition, we briefly discuss the ocular and extraocular phenotypes associated with several other important eye developmental genes, including GDF6, VSX2, RAX, SHH, SIX6 and PAX6.
► Carefully describing the phenotype can aid identification of the correct gene. ► Many of the genes that cause anophthalmia/microphthalmia interact. ► Predicting phenotypes caused by interacting genes is complicated. ► Mutations in causative genes can be non-penetrant or vary in expressivity. ► Modifier genes, epigenetic factors and environment can influence clinical features.
Bardet‐Biedl syndrome (BBS) is a rare ciliopathy characterized by rod‐cone dystrophy, postaxial polydactyly, truncal obesity and renal anomalies with autosomal recessive inheritance. We describe a ...6‐year‐old male with early onset retinal dystrophy, postaxial polydactyly, truncal obesity and motor delays. Exome sequencing revealed a homozygous variant predicted to affect splicing of the IFT74 gene, c.1685‐1G > T. This is the third patient with BBS due to variants predicting loss of function in IFT74. All three patients have had retinal dystrophy, polydactyly, obesity, developmental differences, and a notable lack of renal anomalies. We recommend that IFT74 is added to gene panels for the diagnosis of BBS.
Abstract Congenital diaphragmatic hernia (CDH) is a common birth defect with a high mortality and morbidity. Although numerous chromosomal aberrations and gene mutations have been associated with ...CDH, the etiology of the diaphragmatic defect is identified in less than 50% of patients. This review discusses the some of the more frequent, recurrent karyotypic abnormalities in which CDH is a feature, including 15q26, 8p23.1 and 4p16.3 deletions and tetrasomy 12p (Pallister–Killian syndrome), together with some of the syndromes in which CDH is a relatively common feature, including Fryns syndrome, Matthew-Wood syndrome, overgrowth syndromes and Donnai–Barrow syndrome. In the era of genomic technologies, our knowledge of the genes and chromosome regions involved in pathogenesis of CDH is likely to advance significantly.
The cause of most fetal anomalies is not determined prenatally. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. Nonimmune ...hydrops fetalis (NIHF), a fetal abnormality that is often lethal, has numerous genetic causes; the extent to which exome sequencing can aid in its diagnosis is unclear.
We evaluated a series of 127 consecutive unexplained cases of NIHF that were defined by the presence of fetal ascites, pleural or pericardial effusions, skin edema, cystic hygroma, increased nuchal translucency, or a combination of these conditions. The primary outcome was the diagnostic yield of exome sequencing for detecting genetic variants that were classified as either pathogenic or likely pathogenic according to the criteria of the American College of Medical Genetics and Genomics. Secondary outcomes were the percentage of cases associated with specific genetic disorders and the proportion of variants that were inherited.
In 37 of the 127 cases (29%), we identified diagnostic genetic variants, including those for disorders affecting the RAS-MAPK cell-signaling pathway (known as RASopathies) (30% of the genetic diagnoses); inborn errors of metabolism and musculoskeletal disorders (11% each); lymphatic, neurodevelopmental, cardiovascular, and hematologic disorders (8% each); and others. Prognoses ranged from a relatively mild outcome to death during the perinatal period. Overall, 68% of the cases (25 of 37) with diagnostic variants were autosomal dominant (of which 12% were inherited and 88% were de novo), 27% (10 of 37) were autosomal recessive (of which 95% were inherited and 5% were de novo), 1 was inherited X-linked recessive, and 1 was of uncertain inheritance. We identified potentially diagnostic variants in an additional 12 cases.
In this large case series of 127 fetuses with unexplained NIHF, we identified a diagnostic genetic variant in approximately one third of the cases. (Funded by the UCSF Center for Maternal-Fetal Precision Medicine and others; ClinicalTrials.gov number, NCT03412760.).
The family of vertebrate Crumbs proteins, homologous to Drosophila Crumbs (Crb), share large extracellular domains with epidermal growth factor-like repeats and laminin-globular domains, a single ...transmembrane domain, and a short intracellular C-terminus containing a single membrane proximal 4.1/ezrin/radixin/moesin-binding domain and PSD-95/Discs large/ZO-1-binding motifs. There are 3 Crb genes in humans - Crumbs homolog-1 (CRB1), Crumbs homolog-2 (CRB2), and Crumbs homolog-3 (CRB3). Bilallelic loss-of-function mutations in CRB1 cause visual impairment, with Leber's congenital amaurosis and retinitis pigmentosa, whereas CRB2 mutations are associated with raised maternal serum and amniotic fluid alpha feto-protein levels, ventriculomegaly/hydrocephalus, and renal disease, ranging from focal segmental glomerulosclerosis to congenital Finnish nephrosis. CRB3 has not yet been associated with human disease. In this review, we summarize the phenotypic findings associated with deleterious sequence variants in CRB1 and CRB2. We discuss the mutational spectrum, animal models of loss of function for both genes and speculate on the likely mechanisms of disease.
As new genes for A/M are identified in the genomic era, the number of syndromes associated with A/M has greatly expanded. In this review, we provide a brief synopsis of the clinical presentation and ...molecular genetic etiology of previously characterized pathways involved in A/M, including the Sex-determining region Y-box 2 (
SOX2
), Orthodenticle Homeobox 2 (
OTX2
) and Paired box protein-6 (
PAX6
) genes, and the Stimulated by retinoic acid gene 6 homolog (
STRA6
), Aldehyde Dehydrogenase 1 Family Member A3 (
ALDH1A3
), and RA Receptor Beta (
RARβ
) genes that are involved in retinoic acid synthesis. Less common genetic causes of A/M, including genes involved in BMP signaling Bone Morphogenetic Protein 4 (
BMP4)
, Bone Morphogenetic Protein 7 (
BMP7
) and SPARC-related modular calcium-binding protein 1 (
SMOC1
), genes involved in the mitochondrial respiratory chain complex Holocytochrome c-type synthase (
HCCS
), Cytochrome C Oxidase Subunit 7B (
COX7B
), and NADH:Ubiquinone Oxidoreductase subunit B11 (
NDUFB11
), the BCL-6 corepressor gene (
BCOR
), Yes-Associated Protein 1 (
YAP1
) and Transcription Factor AP-2 Alpha (
TFAP2α
), are more briefly discussed. We also review several recently described genes and pathways associated with A/M, including Smoothened (
SMO
) that is involved in Sonic hedgehog (
SHH
) signaling, Structural maintenance of chromosomes flexible hinge domain containing 1 (
SMCHD1
) and Solute carrier family 25 member 24 (
SLC25A24
), emphasizing phenotype–genotype correlations and shared pathways where relevant.
Abstract
Background: TASP1 encodes an endopeptidase activating histone methyltransferases of the KMT2 family. Homozygous loss-of-function variants in TASP1 have recently been associated with ...Suleiman-El-Hattab syndrome. We report six individuals with Suleiman-El-Hattab syndrome and provide functional characterization of this novel histone modification disorder in a multi-omics approach. Methods: Chromosomal microarray/exome sequencing in all individuals. Western blotting from fibroblasts in two individuals. RNA sequencing and proteomics from fibroblasts in one individual. Methylome analysis from blood in two individuals. Knock-out of tasp1 orthologue in zebrafish and phenotyping. Results: All individuals had biallelic TASP1 loss-of-function variants and a phenotype including developmental delay, multiple congenital anomalies (including cardiovascular and posterior fossa malformations), a distinct facial appearance and happy demeanor. Western blot revealed absence of TASP1. RNA sequencing/proteomics showed HOX gene downregulation (HOXA4, HOXA7, HOXA1 and HOXB2) and dysregulation of transcription factor TFIIA. A distinct methylation profile intermediate between control and Kabuki syndrome (KMT2D) profiles could be produced. Zebrafish tasp1 knock-out revealed smaller head size and abnormal cranial cartilage formation in tasp1 crispants. Conclusion: This work further delineates Suleiman-El-Hattab syndrome, a recognizable neurodevelopmental syndrome. Possible downstream mechanisms of TASP1 deficiency include perturbed HOX gene expression and dysregulated TFIIA complex. Methylation pattern suggests that Suleiman-El-Hattab syndrome can be categorized into the group of histone modification disorders including Wiedemann–Steiner and Kabuki syndrome.
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