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Photograph showing the following distinctive facial features: straight eyebrows, bilateral ptosis with the left side being more pronounced than the right, up-slanted palpebral fissures, broad nasal bridge, low-set and posteriorly rotated ears, small mouth, thick lower lip, and microretrognathia
Source publication
Background
Studying human genome using chromosomal microarrays has significantly improved the accuracy and yield of diagnosing genomic disorders. Chromosome 7q36 deletions and duplications are rare genomic disorders that have been reported in a limited number of children with developmental delay, growth retardation, and congenital malformation. Alt...
Citations
... It is possible that the triplication and duplication may have resulted from either two simultaneous events or a two-steps process. The mechanism proposed is almost similar to cases previously reported involving the chromosomes 7 and 15 [26,31,32]. ...
Highly identical segmental duplications (SDs) account for over 5% of the human genome and are enriched in the short arm of the chromosome 16. These SDs are susceptibility factors for recurrent chromosomal rearrangements mediated by non-allelic homologous recombination (NAHR). Chromosomal microarray analysis (CMA) has been widely used as the first-tier test for individuals with developmental disabilities and/or congenital anomalies and several genomic disorders involving the 16p-arm have been identified with this technique. However, the resolution of CMA and the limitations of short-reads whole genome sequencing (WGS) technology do not allow the full characterization of the most complex chromosomal rearrangements. Herein, we report on two unrelated patients with a de novo 16p13.11p11.2 triplication associated with a 16p11.2 duplication, detected by CMA. These patients share a similar phenotype including hypotonia, severe neurodevelopmental delay with profound speech impairment, hyperkinetic behavior, conductive hearing loss, and distinctive facial features. Short-reads WGS could not map precisely any of the rearrangement’s breakpoints that lie within SDs. We used optical genome mapping (OGM) to determine the relative orientation of the triplicated and duplicated segments as well as the genomic positions of the breakpoints, allowing us to propose a mechanism involving recombination between allelic SDs and a NAHR event. In conclusion, we report a new clinically recognizable genomic disorder. In addition, the mechanism of these complex chromosomal rearrangements involving SDs could be unraveled by OGM.
... Another important aspect of GALNT11 is that its expression is related to heterotaxy, a congenital heart disease resulting from abnormalities in left-right body patterning [110]. A case report of a 22-month-old male indicated that GALNT11, together with GALNT20 (GALNTL5), which seems to be a non-functional protein (see below), was associated with developmental delay, distinctive facial features and multiple congenital anomalies [111]. These observations may be related to Notch signaling activation due to Notch1 O-glycosylation by GalNAc-T11 [112]. ...
Mucin-type O-glycosylation involves the attachment of glycans to an initial O-linked N-acetylgalactosamine (GalNAc) on serine and threonine residues on proteins. This process in mammals is initiated and regulated by a large family of 20 UDP-GalNAc: polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts) (EC 2.4.1.41). The enzymes are encoded by a large gene family (GALNTs). Two of these genes, GALNT2 and GALNT3, are known as monogenic autosomal recessive inherited disease genes with well characterized phenotypes, whereas a broad spectrum of phenotypes is associated with the remaining 18 genes. Until recently, the overlapping functionality of the 20 members of the enzyme family has hindered characterizing the specific biological roles of individual enzymes. However, recent evidence suggests that these enzymes do not have full functional redundancy and may serve specific purposes that are found in the different phenotypes described. Here, we summarize the current knowledge of GALNT and associated phenotypes.
... Of those genes linked to an alternative splicing event during growth inhibition, several have already been broadly implicated in myopia development, including PER3 (period circadian clock 3) 65,66 and TDRD9 (tudor domain containing 9). 66 Several others are associated with neuromodulators implicated in ocular growth regulation (for review see Ref. [4]), including GABA (GABRB2) as well as the dopamine and glutamate systems (phospholipase C beta 4 [PLCB4]). Finally, five of the genes have also been reported to show an association with high myopia in humans (GABRB2, 67 PPP1R3B, 68 COL11A1, 69,70 GALNT11, 71 and PLCB4 72 ). ...
Myopia (short‐sightedness), usually caused by excessive elongation of the eye during development, has reached epidemic proportions worldwide. In animal systems including the chicken model, several treatments have been shown to inhibit ocular elongation and experimental myopia. Although diverse in their apparent mechanism of action, each one leads to a reduction in the rate of ocular growth. We hypothesize that a defined set of retinal molecular changes may underlie growth inhibition, irrespective of the treatment agent used. Accordingly, across five well‐established but diverse methods of inhibiting myopia, significant overlap is seen in the retinal transcriptome profile (transcript levels and alternative splicing events) in chicks when analyzed by RNA‐seq. Within the two major pathway networks enriched during growth inhibition, that of cell signaling and circadian entrainment, transcription factors form the largest functional grouping. Importantly, a large percentage of those genes forming the defined retinal response are downstream targets of the transcription factor EGR1 which itself shows a universal response to all five growth‐inhibitory treatments. This supports EGR1's previously implicated role in ocular growth regulation. Finally, by contrasting our data with human linkage and GWAS studies on refractive error, we confirm the applicability of our study to the human condition. Together, these findings suggest that a universal set of transcriptome changes, which sit within a well‐defined retinal network that cannot be bypassed, is fundamental to growth regulation, thus paving a way for designing novel targets for myopia therapies.
... Altered dosages of SHH and HLXB9, both located in 7q36.3, are believed to play roles in the phenotypes associated with these rearrangements. Al Dhaibani et al. [37] reported a chromosome 7q36.1-q36.2 triplication in a child with IUGR complications prenatally and with developmental delay, distinctive facial features, and multiple congenital complications postnatally. ...
... triplication in a child with IUGR complications prenatally and with developmental delay, distinctive facial features, and multiple congenital complications postnatally. The increased GALNT11 dosage potentially alters the Notch signaling pathway, explaining the pathogenicity of 7q36 triplication [37]. Upon querying the database, we believed that the phenotype of this case was consistent with chromosome 7q21.13-q36.3 ...
Background
This study was an evaluation of the role of noninvasive prenatal testing (NIPT) in the detection of trisomy 7 in prenatal diagnosis.
Method
A total of 35 consecutive cases underwent screening for trisomies by cell-free DNA testing between April 2015 and November 2017 due to suspicious NIPT results; these cases represented 0.11% of patients (35/31,250) with similar frequencies of abnormal results among the laboratories performing the tests. NIPT was offered to further screen for common fetal chromosomal abnormalities. Karyotype analysis, chromosomal microarray analysis (CMA), and next-generation sequencing (NGS) were used to detect 20, 14, and 25 patients, respectively, who accepted confirmatory diagnostic testing.
Results
High-risk results by NIPT were recorded for trisomy 7 alone in 29 women: dual aneuploidy in 4 patients and multiple aneuploidy in 2 patients. Karyotype analysis of amniotic fluid cells was normal in all 20 pregnancies, suggesting a probability of confined placental mosaicism. Further CMA data were obtained in 14 of the cases mentioned above, and 2 fetuses were detected with positive results with copy number variation. The NGS results suggested that all these samples were placental chimerisms of chromosome 7, except for one sample that was found to be an additional chimerism of chromosome 2, which was also consistent with the NIPT result.
Conclusion
Our results may be useful for the counseling of pregnant women in the detection of trisomy 7 by NIPT.
... One such recent report on de-novo 7q36.1q36.2 triplication suggested association of the increased dosage of GALNT11 gene with multi-organ manifestations, due to alterations in the Notch signaling pathway that influence organogenesis and morphogenesis [13]. Another important gene in this region is the sonic hedgehog (SHH) gene (at 7q36) which codes for sonic hedgehog protein that is involved in the morphogenesis of the developing embryo. ...
Background:
Parental balanced reciprocal translocations can result in partial aneuploidies in the offspring due to unbalanced meiotic segregation during gametogenesis. Herein, we report the phenotypic and molecular cytogenetic characterization of a 2 years and 4 months old female child with partial trisomy 7q22 → qter. This is the first such reported case resulting from a parental balanced translocation involving the long arms of chromosomes 7 and 14. The phenotype of the proband was compared with that of previously reported cases of trisomy 7q21 → qter or 7q22 → qter resulting from parental balanced translocations.
Case presentation:
The proband was born pre-term to a 34-year-old mother with a history of two first trimester miscarriages and an early infant death. She was referred at the age of 8 months for genetic evaluation due to prenatal and postnatal growth retardation, developmental delay and multiple congenital anomalies. On clinical evaluation, she had craniofacial dysmorphic features such as scaphocephaly, large anterior fontanelle with open posterior fontanelle, prominent occiput, triangular face, high forehead, hypertelorism, down slanting eyes, flat nasal bridge, small nose, low set ears, micro-retrognathia, high arched palate and short neck. Cranial computerized tomography scan showed lateral ventriculomegaly with features of early cerebral atrophy. Conventional cytogenetic analysis showed the karyotype 46,XX,der(14)t(7;14)(q22;q32)mat in the proband due to an unbalanced segregation of a maternal balanced translocation t(7;14)(q22;q32). Fluorescence in-situ hybridization analysis confirmed the partial trisomy 7q22 → qter in the proband with a minimal loss of genetic material on chromosome 14. Single nucleotide polymorphism array further confirmed the duplication on chromosome 7q22.1 → qter and a small terminal deletion on chromosome 14q32.3 → qter.
Conclusion:
We report the longest-surviving child with trisomy 7q22 → qter due to a parental balanced translocation between chromosomes 7 and 14. Clinical features observed in the proband were consistent with the consensus phenotype of partial trisomy 7q22 → qter reported in the scientific literature. Early diagnosis of these patients using molecular cytogenetic techniques is important for establishing the precise diagnosis and for making decisions pertaining to the prognostication and management of affected individuals.
Background
Congenital heart disease (CHD) is the most common type of birth defects. Genetic factors are the important contributor to the etiology of CHD. However, the underlying genetic causes in most individuals remain unclear.
Methods
101 individuals with CHD and their unaffected parents were included in this study. Chromosome microarray analysis (CMA) as a first-tier clinical diagnostic tool was applied for all affected individuals, followed by trio-based whole exome sequencing (WES). The function of the genes involved in the genetic variants in the cohort was analyzed.
Results
We detected aneuploidies in 2 individuals (trisomy 21 and monosomy X), other pathogenic/likely pathogenic copy number variants (CNVs) in 20 individuals, and pathogenic /likely pathogenic SNVs/InDels in 9 individuals. The combined genetic diagnostic yield was 30.7%, including 21.8% with chromosomal abnormalities and 8.9% with sequence-level variants. Nineteen CNVs in 19 individuals were associated with 14 recurrent chromosomal microdeletion/microduplication syndromes, the most common being 22q11.2 deletion syndrome. Pathogenic/likely pathogenic sequence-level variants were identified in nine genes, including GATA6, FLNA, KANSL1, HNRNPK, TRAF7, KAT6A, PKD1L1, RIT1, and SMAD6. The function of the genes involved in the CHD relevant CNVs and SNVs was analyzed indicating enriched genes are mainly associated with development of multiple organs, not only heart, but also brain and endocrine system.
Conclusions
CMA is a first-tier clinical diagnostic test to define the underlying genomic architecture of CHD. Trio-based WES increases the diagnostic yield, and should be part of the diagnostic algorithm. Our study expands the genes interaction networks for genetic study of CHD.
Myopia has become one of the most critical health problems in the world with the increasing time spent indoors and increasing close work. Pathological myopia may have multiple complications, such as myopic macular degeneration, retinal detachment, cataracts, open-angle glaucoma, and severe cases that can cause blindness. Mounting evidence suggests that the cause of myopia can be attributed to the complex interaction of environmental exposure and genetic susceptibility. An increasing number of researchers have focused on the genetic pathogenesis of myopia in recent years. Scleral remodeling and excessive axial elongating induced retina thinning and even retinal detachment are myopia's most important pathological manifestations. The related signaling pathways are indispensable in myopia occurrence and development, such as dopamine, nitric oxide, TGF-β, HIF-1α, etc. We review the current major and recent progress of biomedicine on myopia-related signaling pathways and mechanisms.
Pure distal duplications of 7q have rarely been described in the medical literature. The term pure refers to duplications that occur without an accompanying clinically significant deletion. Pure 7q duplications of various segments have previously been reported in the literature; however, pure distal 7q duplications have only been reported in 21 cases. Twenty of these earlier reports described patients who were identified via karyotype and 1 recently by microarray. Cases have also been reported in genomic databases such as DECIPHER and the University of California Santa Cruz genome browser. We have reviewed 7 additional cases with distal 7q duplications from these databases and compared them to 7 previously reported distal 7q duplication cases to uncover common features including global developmental delay, frontal bossing, macrocephaly, seizures, kyphoscoliosis/skeletal anomalies, and microretrognathia/palatal anomalies. In this case, we describe a 4-year-old boy with a 30.8-Mb pure duplication of 7q32.1q36.3. Newly reported features associated with this duplication include intermittent dystonic posturing, increased behavioral irritability, eosinophilic esophagitis, segmental vertebral anomalies, and segmental intermittent limb cyanosis. We highlight the importance of using publicly available databases to describe rare genetic syndromes and to better characterize the features of pure distal 7q duplications and further postulate that duplication of this region represents a recognizable macrocephalic neurodevelopmental syndrome.
Objective:
Copy number variation (CNV) has been associated with idiopathic short stature, small for gestational age and Silver-Russell syndrome (SRS). It has not been extensively investigated in growth hormone insensitivity (GHI; short stature, IGF-1 deficiency and normal/high GH) or previously in IGF-1 insensitivity (short stature, high/normal GH and IGF-1).
Design and methods:
Array comparative genomic hybridisation was performed with ~60 000 probe oligonucleotide array in GHI (n = 53) and IGF-1 insensitivity (n = 10) subjects. Published literature, mouse models, DECIPHER CNV tracks, growth associated GWAS loci and pathway enrichment analyses were used to identify key biological pathways/novel candidate growth genes within the CNV regions.
Results:
Both cohorts were enriched for class 3-5 CNVs (7/53 (13%) GHI and 3/10 (30%) IGF-1 insensitivity patients). Interestingly, 6/10 (60%) CNV subjects had diagnostic/associated clinical features of SRS. 5/10 subjects (50%) had CNVs previously reported in suspected SRS: 1q21 (n = 2), 12q14 (n = 1) deletions and Xp22 (n = 1), Xq26 (n = 1) duplications. A novel 15q11 deletion, previously associated with growth failure but not SRS/GHI was identified. Bioinformatic analysis identified 45 novel candidate growth genes, 15 being associated with growth in GWAS. The WNT canonical pathway was enriched in the GHI cohort and CLOCK was identified as an upstream regulator in the IGF-1 insensitivity cohorts.
Conclusions:
Our cohort was enriched for low frequency CNVs. Our study emphasises the importance of CNV testing in GHI and IGF-1 insensitivity patients, particularly GHI subjects with SRS features. Functional experimental evidence is now required to validate the novel candidate growth genes, interactions and biological pathways identified.
Chromosomal triplications can be classified into recurrent and non-recurrent triplications. Most of the non-recurrent triplications are embedded in duplicated segments, and duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) has been established as one of the mechanisms of triplication. This study aimed to reveal the underlying mechanism of the TRP-DUP-TRP pattern of chromosomal aberrations, in which the appearance of moving averages obtained through array-based comparative genomic hybridization analysis is similar to the shadows of the caldera volcano-like pattern, which were first identified in two patients with neurodevelopmental disabilities. For this purpose, whole-genome sequencing using long-read Nanopore sequencing was carried out to confirm breakpoint junctions. Custom array analysis and Sanger sequencing were also used to detect all breakpoint junctions. As a result, the TRP-DUP-TRP pattern consisted of only two patterns of breakpoint junctions in both patients. In patient 1, microhomologies were identified in breakpoint junctions. In patient 2, more complex architectures with insertional segments were identified. Thus, replication-based mechanisms were considered as a mechanism of the TRP-DUP-TRP pattern. This article is protected by copyright. All rights reserved.
