Mild Facial Dysmorphism Research Articles

Prenatal diagnosis of a fetus with 15q11q13 complex duplication syndrome and a literature review

To explore the clinical features and genetic etiology of a fetus with 15q11q13 complex duplication syndrome. A fetus diagnosed with 15q11q13 duplication syndrome at Ningbo Women and Children's Hospital on April 19, 2023 was selected as the study subject. Clinical data was collected, and the fetus was subjected to invasive prenatal diagnosis including G-banded karyotyping and chromosomal microarray analysis (CMA). Following the discovery of chromosomal duplication, trio-whole exome sequencing was carried out to exclude single base variants and confirm the parental original of the duplication. Optical genome mapping was also performed to delineate the structural arrangement of the duplication. Relevant literature was searched in the PubMed, Wanfang Medical Network and CNKI databases using "15q11q13", "duplication", "hexasomy" and "Six fold repetition" as the key words from January 1, 2000 to August 1, 2023 for a review of previously reported 15q11q13 hexasomy cases. This study was approved by the Ningbo Women & Children's Hospital (Ethics No. EC2020-048). The fetus was found to have a mosaicism karyotype of 48,X?,+mar,+idic(15)(q13)[33]/47,X?,+idic(15)(q13)[17]. CMA and trio-WES have all shown a six-fold duplication in the PWS/AS critical region (PWACR) at 15q11.2q13.2 and quadruple duplication of 15q13.2q13.3 region, which have derived from its mother and formed supernumerary marker chromosomes (SMCs). Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the 15q11.2q13.2 sixfold duplication was classified as pathogenic, whilst the 15q13.2q13.3 quadruple duplication was classified as variant of uncertain significance. Literature search has identified 11 cases of 15q11q13 duplication involving hexasomy of the PWACR, with all cases showing mental retardation, language delay and hypotonia, and most of them also had motor retardation, epilepsy and mild facial dysmorphism. Hexasomy for the PWACR combined with tetrasomy of 15q13.2q13.3 probably underlay the left hand polydactyly, polyhydramnios and intrauterine growth retardation in this fetus.

Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling

BackgroundSETBP1 Haploinsufficiency Disorder (SETBP1-HD) is characterised by mild to moderate intellectual disability, speech and language impairment, mild motor developmental delay, behavioural issues, hypotonia, mild facial dysmorphisms, and vision impairment. Despite a clear link between SETBP1 mutations and neurodevelopmental disorders the precise role of SETBP1 in neural development remains elusive. We investigate the functional effects of three SETBP1 genetic variants including two pathogenic mutations p.Glu545Ter and SETBP1 p.Tyr1066Ter, resulting in removal of SKI and/or SET domains, and a point mutation p.Thr1387Met in the SET domain.MethodsGenetic variants were introduced into induced pluripotent stem cells (iPSCs) and subsequently differentiated into neurons to model the disease. We measured changes in cellular differentiation, SETBP1 protein localisation, and gene expression changes.ResultsThe data indicated a change in the WNT pathway, RNA polymerase II pathway and identified GATA2 as a central transcription factor in disease perturbation. In addition, the genetic variants altered the expression of gene sets related to neural forebrain development matching characteristics typical of the SETBP1-HD phenotype.LimitationsThe study investigates changes in cellular function in differentiation of iPSC to neural progenitor cells as a human model of SETBP1 HD disorder. Future studies may provide additional information relevant to disease on further neural cell specification, to derive mature neurons, neural forebrain cells, or brain organoids.ConclusionsWe developed a human SETBP1-HD model and identified perturbations to the WNT and POL2RA pathway, genes regulated by GATA2. Strikingly neural cells for both the SETBP1 truncation mutations and the single nucleotide variant displayed a SETBP1-HD-like phenotype.

Prenatal detection of distal 18p deletion by chromosomal microarray analysis: Three case reports and literature review.

Chromosome 18p deletion syndrome is caused by total or partial deletion of the short arm of chromosome 18 and associated with cognitive impairment, growth retardation and mild facial dysmorphism. However, most studies on the genotype-phenotype correlations in the 18p region are diagnosed postnatally. Prenatal reports involving 18p deletions are limited. Three pregnant women opted for invasive prenatal testing due to noninvasive prenatal testing indicating high risk for chromosome 18 abnormalities. Karyotypic analysis and chromosomal microarray analysis (CMA) were performed simultaneously. The pregnancy outcomes for all cases were followed up. Meanwhile, we also made a literature review on prenatal phenotypes of 18p deletions. G-banding analysis showed that 2 fetuses presented abnormal karyotypes: 45,XN,der(18)t(18;21)(p11; q11),-21 (case 2) and 46,XN,18p- (case 3). The karyotype of case 1 was normal. Meanwhile, CMA detected 4.37 Mb (case 1), 7.26 Mb (case 2) and 14.97 Mb (case 3) deletions in chromosome 18p region. All 3 pregnancies were terminated finally according to genetic counseling based upon abnormal CMA results. Prenatal diagnosis of 18p deletion syndrome is full of challenges due to the phenotypic diversity, incomplete penetrance and lack of prenatal phenotypes. Increased nuchal translucency and holoprosencephaly are common prenatal phenotypes of distal 18p deletion. For fetuses carrying 18p deletions with atypical sonographic phenotypes, noninvasive prenatal testing could be adopted as an effective approach.

Genome Sequencing of Idiopathic Speech Delay

Genetic investigations of people with speech and language disorders can provide windows into key aspects of human biology. Most genomic research into impaired speech development has so far focused on childhood apraxia of speech (CAS), a rare neurodevelopmental disorder characterized by difficulties with coordinating rapid fine motor sequences that underlie proficient speech. In 2001, pathogenic variants of FOXP2 provided the first molecular genetic accounts of CAS aetiology. Since then, disruptions in several other genes have been implicated in CAS, with a substantial proportion of cases being explained by high-penetrance variants. However, the genetic architecture underlying other speech-related disorders remains less well understood. Thus, in the present study, we used systematic DNA sequencing methods to investigate idiopathic speech delay, as characterized by delayed speech development in the absence of a motor speech diagnosis (such as CAS), a language/reading disorder, or intellectual disability. We performed genome sequencing in a cohort of 23 children with a rigorous diagnosis of idiopathic speech delay. For roughly half of the sample (ten probands), sufficient DNA was also available for genome sequencing in both parents, allowing discovery of de novo variants. In the thirteen singleton probands, we focused on identifying loss-of-function and likely damaging missense variants in genes intolerant to such mutations. We found that one speech delay proband carried a pathogenic frameshift deletion in SETD1A, a gene previously implicated in a broader variable monogenic syndrome characterized by global developmental problems including delayed speech and/or language development, mild intellectual disability, facial dysmorphisms, and behavioural and psychiatric symptoms. Of note, pathogenic SETD1A variants have been independently reported in children with CAS in two separate studies. In other probands in our speech delay cohort, likely pathogenic missense variants were identified affecting highly conserved amino acids in key functional domains of SPTBN1 and ARF3. Overall, this study expands the phenotype spectrum associated with pathogenic SETD1A variants, to also include idiopathic speech delay without CAS or intellectual disability, and suggests additional novel potential candidate genes that may harbour high-penetrance variants that can disrupt speech development.

Confirmation and expansion of the phenotype of the TCEAL1-related neurodevelopmental disorder

Numerous contiguous gene deletion syndromes causing neurodevelopmental disorders have previously been defined using cytogenetics for which only in the current genomic era the disease-causing genes have become elucidated. One such example is deletion at Xq22.2, previously associated with a neurodevelopmental disorder which has more recently been found to be caused by de novo loss-of-function variants in TCEAL1. So far, a single study reported six unrelated individuals with this monogenetic disorder, presenting with syndromic features including developmental delay especially affecting expressive speech, intellectual disability, autistic-like behaviors, hypotonia, gait abnormalities and mild facial dysmorphism, in addition to ocular, gastrointestinal, and immunologic abnormalities. Here we report on four previously undescribed individuals, including two adults, with de novo truncating variants in TCEAL1, identified through trio exome or genome sequencing, further delineating the phenotype of the TCEAL1-related disorder. Whereas overall we identify similar features compared to the original report, we also highlight features in our adult individuals including hyperphagia, obesity, and endocrine abnormalities including hyperinsulinemia, hyperandrogenemia, and polycystic ovarian syndrome. X chromosome inactivation and RNA-seq studies further provide functional insights in the molecular mechanisms. Together this report expands the phenotypic and molecular spectrum of the TCEAL1-related disorder which will be useful for counseling of newly identified individuals and their families.

Homozygous DBF4 mutation as a cause of severe congenital neutropenia

Severe congenital neutropenia presents with recurrent infections early in life as a result of arrested granulopoiesis. Multiple genetic defects are known to block granulocyte differentiation; however, a genetic cause remains unknown in approximately 40% of cases. We aimed to characterize a patient with severe congenital neutropenia and syndromic features without a genetic diagnosis. Whole exome sequencing results were validated using flow cytometry, Western blotting, coimmunoprecipitation, quantitative PCR, cell cycle and proliferation analysis of lymphocytes and fibroblasts and granulocytic differentiation of primary CD34+ and HL-60 cells. We identified a homozygous missense mutation in DBF4 in a patient with mild extra-uterine growth retardation, facial dysmorphism and severe congenital neutropenia. DBF4 is the regulatory subunit of the CDC7 kinase, together known as DBF4-dependent kinase (DDK), the complex essential for DNA replication initiation. The DBF4 variant demonstrated impaired ability to bind CDC7, resulting in decreased DDK-mediated phosphorylation, defective S-phase entry and progression and impaired differentiation of granulocytes associated with activation of the p53-p21 pathway. The introduction of wild-type DBF4 into patient CD34+ cells rescued the promyelocyte differentiation arrest. Hypomorphic DBF4 mutation causes autosomal-recessive severe congenital neutropenia with syndromic features.

Two siblings with Bosch-Boonstra-Schaaf optic atrophy syndrome due to parental gonadal mosaicism

Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS, OMIM 615722) is a rare autosomal dominant disorder characterized by intellectual disability, optic atrophy, cortical visual impairment, mild facial dysmorphism, hypotonia, hearing problems, attention deficit and a thin corpus callosum. The gene underlying this disorder is NR2F1 located on chromosome 5q15 which encodes for a nuclear receptor protein. Mutations and deletions have been identified in patients. Here we report on a brother and a sister carrying a pathogenic nonsense NR2F1 variant. The patients have a mild phenotype showing optic atrophy, mild intellectual disability, dysmorphic features and thin corpus callosum. This correlates with previously described milder phenotypes in patients with mutations in this domain. The variant was not identified in the parental genome indicating most likely a gonadal mosaicism. Gonadal mosaicism has not yet been reported in Bosch-Boonstra-Schaaf Optic Atrophy Syndrome.

498 PERSISTENT FIFTH AORTIC ARCH IN A PATIENT WITH CHARGE SYNDROME: A CASE REPORT AND SYSTEMATIC REVIEW OF LITERATURE

Abstract Background CHARGE syndrome (CS) is a rare genetic disease characterized by a constellation of clinical findings including Coloboma, Heart defects, choanal Atresia, Retardation of growth and/or development, Genitourinary malformation and Ear abnormalities. We present a case of persistent fifth aortic arch (PFAA), an extremely rare congenital anomaly of aortic arch (AA), in a child with genetically confirmed CS and perform a systematic review of published studied, in an effort to examinate the distribution of congenital heart diseases (CHDs) and their impact in CHARGE patients. Case presentations and results A 12 years-old child was referred to our echocardiography laboratory for atypical chest pain. He had bilateral ocular coloboma, left hypoacusis, scoliosis, mild motor impairments, nocturnal enuresis, micropenis and facial dysmorphisms. Molecular diagnostic testing identified a de novo mutation (variant c.5290_5300+10del) in the CHD7 gene and CS was diagnosed. Echocardiography showed a single posterolateral papillary muscle and a cleft of anterior mitral leaflet. Interestingly, AA had a double-lumen appearance without Doppler signs of coarctation. A PFFA was hypothesized and then confirmed at angioCT. A systematic review of the literature was performed according to PRISMA guidelines. All published articles reporting the association CS and CHDs were chosen. A total of 975 records were identified. After the screening of title and abstract, assessed for eligibility were 219 papers. Finally, inclusion and full-text analysis was made in 60 studies, of which 37 case reports and 23 case series. We found that ventricular septal defects emerged as the most prevalent heart defect (32%), followed by atrial septal defects reported in 23% of cases. Complex CHDs were also described. Interestingly, AA abnormalities were reported in a high percentage (27%) of patients, right AA in 20% in association or not with aberrant subclavian artery and vascular ring, interrupted AA in 5% of cases, as well as aortic coarctation in 10%. Of note, almost half of the cases (49%) required cardiac surgery, mostly performed within 1 year from birth and, although outcome was available in a minority of patients, the death was reported in almost 30%. Conclusions Our case is the first that reports PFFA in CS and may be mistaken for AA dissection. In comparison with other syndromic diseases, a high prevalence of AA abnormalities was found in patients with mutations in the CHD7 gene.

New insights into candidate genes for autism spectrum disorder in 8p23.1 duplication syndrome

The 8p23.1 duplication syndrome is a rare condition, characterized by dysmorphisms, intellectual disability, congenital cardiac anomalies, and autism spectrum disorder (ASD). The current model for explaining the pathogenesis of this condition postulates that few dosage-sensitive genes within the duplication are sufficient for the core clinical features, although the molecular mechanisms leading to the ASD presentation remain to be solved. Herein, we described clinical and cytomolecular findings of an 8p23.1 duplication in a boy with mild facial dysmorphisms, cardiac anomalies and ASD. Therefore, we investigated the influence of duplicated genes on the pathophysiology of ASD in our patient. We identified four duplicated genes (BLK, GATA4, PINX1, TNKS) connected with proteins previously associated with ASD and involved in significant enriched pathways associated with human neurological conditions. Moreover, the candidate genes are highly expressed in brain regions associated to ASD, such as the hippocampus. Taken together, these results point out crucial interactions among BLK, GATA4, PINX1, and TNKS and genes associated with ASD. We indicate cellular networks perturbations encompassing neuronal development pathways related to our patient's condition. Thus, these findings bring new insights into the genetic basis of ASD in patients with 8p23.1 duplication syndrome.

PMON193 Reactive oxygen species in the development of gonadal failure in late-onset transaldolase deficiency

Abstract Background Deficiency in Transaldolase, an essential enzyme in regulating NADPH and ribose 5-phosphate production, has been reported in only 39 patients to date. Most patients present already prenatally/neonatally with intra uterine growth retardation, hepato(spleno)megaly and consequent liver failure, anemia, thrombocytopenia, dysmorphic facial features, cardiac and skin abnormalities and hypergonadotropic hypogonadism in cases of late-onset presentation. The mechanism underlying gonadal dysfunction is not fully understood. Clinical case, methods and results A 15y old male from an Indian-Jewish background, with atrial-septal-defect, renal tubulopathy, mild facial dysmorphism and transient liver enzymes abnormalities presented with absence of pubertal development. His gonadotropins levels were elevated (LH – 22 IU/L, FSH 103 IU/L) while testosterone was low. Whole exome sequencing revealed homozygous variant in a novel T167M missense mutation in TALDO1 (transaldolase) gene whereas both parents were heterozygote carriers. Proteine structure analysis indicate that Threonine 167 is part of transaldolase catalytic site and critical for its function. As transaldolase activity is required for nucleic acids production, NADPH synthesis and reduction of cellular Reactive Oxygen Species (ROS) we measured the ROS accumulation using 2′,7′-dichlorodihydrofluorescein diacetate, in fibroblasts derived from the patient and normal controls. The affected patient's fibroblasts showed a significantly increased accumulation of ROS (207%, P=0.007), compared to controls indicating an increased susceptibility to oxidative stress. Conclusion The novel T167M missense mutation in the transaldolase (TALDO1) gene causes a unique clinical presentation including a relative mild liver involvement and hypergonadotrophic hypogonadism. The compromised TALDO1 activity in preventing cellular ROS accumulation in actual patient's fibroblasts is shown here for the first time and may indicate the therapeutic use of antioxidants in all patients with TALDO1 dysfunction. The high expression of TALDO1 in the testis and the gonadal failure suggests its tissue specific requirement in preventing the accumulation of ROS during steroidogenesis. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

The recurrent de novo c.2011C>T missense variant in MTSS2 causes syndromic intellectual disability

MTSS2, also known as MTSS1L, binds to plasma membranes and modulates their bending. MTSS2 is highly expressed in the central nervous system (CNS) and appears to be involved in activity-dependent synaptic plasticity. Variants in MTSS2 have not yet been associated with a human phenotype in OMIM. Here we report five individuals with the same heterozygous de novo variant in MTSS2 (GenBank: NM_138383.2: c.2011C>T [p.Arg671Trp]) identified by exome sequencing. The individuals present with global developmental delay, mild intellectual disability, ophthalmological anomalies, microcephaly or relative microcephaly, and shared mild facial dysmorphisms. Immunoblots of fibroblasts from two affected individuals revealed that the variant does not significantly alter MTSS2 levels. We modeled the variant in Drosophila and showed that the fly ortholog missing-in-metastasis (mim) was widely expressed in most neurons and a subset of glia of the CNS. Loss of mim led to a reduction in lifespan, impaired locomotor behavior, and reduced synaptic transmission in adult flies. Expression of the human MTSS2 reference cDNA rescued the mim loss-of-function (LoF) phenotypes, whereas the c.2011C>T variant had decreased rescue ability compared to the reference, suggesting it is a partial LoF allele. However, elevated expression of the variant, but not the reference MTSS2 cDNA, led to similar defects as observed by mim LoF, suggesting that the variant is toxic and may act as a dominant-negative allele when expressed in flies. In summary, our findings support that mim is important for appropriate neural function, and that the MTSS2 c.2011C>T variant causes a syndromic form of intellectual disability.

A new FOXE1 homozygous frameshift variant expands the genotypic and phenotypic spectrum of Bamforth–Lazarus syndrome

Bamforth-Lazarus syndrome is a rare autosomal recessive disease caused by biallelic loss-of-function variants in the FOXE1 gene. The condition is characterized by congenital hypothyroidism due to thyroid agenesis or thyroid hypoplasia, cleft palate, spiky hair, with or without choanal atresia, and bifid epiglottis. To date, seven pathogenic variants have been reported in the FOXE1 gene causing Bamforth-Lazarus syndrome. Here we report a novel homozygous loss-of-function variant in the FOXE1 gene NM_004473.4:c.141dupC:p.(Leu49Profs*75) leading to congenital hypothyroidism due to thyroid agenesis, scalp hair abnormalities, cleft palate, small areola, cafe-au-lait spots, mild bilateral hearing loss, skin abnormalities, and facial dysmorphism. We describe the evolving phenotype in the patient with age and review previous variants reported in FOXE1. This report further expands the clinical and molecular spectrum of Bamforth-Lazarus syndrome.

SMAD3 mutation in LDS3 causes bone fragility by impairing the TGF-β pathway and enhancing osteoclastogenesis

Loss-of-function mutations in SMAD3 cause Loeys-Dietz syndrome type 3 (LDS3), a rare autosomal-dominant connective tissue disorder characterized by vascular pathology and skeletal abnormalities. Dysregulation of TGF-β/SMAD signaling is associated with abnormal skeletal features and bone fragility. To date, histomorphometric and ultrastructural characteristics of bone with SMAD3 mutations have not been reported in humans and the exact mechanism by which SMAD3 mutations cause the LDS3 phenotype is poorly understood. Here, we investigated bone histomorphometry and matrix mineralization in human bone with a SMAD3 mutation and explored the associated cellular defect in the TGF-β/SMAD pathway in vitro. The index patient had recurrent fractures, mild facial dysmorphism, arachnodactyly, pectus excavatum, chest asymmetry and kyphoscoliosis. Bone histomorphometry revealed markedly reduced cortical thickness (−68 %), trabecular thickness (−32 %), bone formation rate (−50 %) and delayed mineralization. Quantitative backscattered electron imaging demonstrated undermineralized bone matrix with increased heterogeneity in mineralization. The patient's SMAD3 mutation (c.200 T > G; p.I67S), when expressed from plasmid vectors in HEK293 cells, showed reduced phosphorylation and transcription factor activity compared to normal control and SMAD3 (p.S264Y), a gain-of-function mutation, somatic mosaicism of which causes melorheostosis. Transfection study of the patients' SMAD3 (p.I67S) mutation displayed lower luciferase reporter activity than normal SMAD3 and reduced expression of TGF-β signaling target genes. Patient fibroblasts also demonstrated impaired SMAD3 protein stability. Osteoclastogenic differentiation significantly increased and osteoclast-associated genes, including ACP5 (encoding TRAP), ATP6V0D2, and DCSTAMP, were up-regulated in CD14 (+) peripheral blood mononuclear cells (PBMCs) with the SMAD3 (p.I67S) mutation. Upregulation of osteoclastogenic genes was associated with decreased expression of TGF-β signaling target genes. We conclude that bone with the SMAD3 (p.I67S) mutation features reduced bone formation, and our functional studies revealed decreased SMAD3 activation and protein stability as well as increased osteoclastogenesis. These findings enhance our understanding of the pathophysiology of LDS3 caused by SMAD3 mutations. Emerging therapies targeting in the TGF-β/SMAD pathway also raise hope for treatment of LDS3.

Partial CHARGE syndrome with bilateral retinochoroidal colobomas associated with 7q11.23 duplication syndrome: case report

BackgroundCHARGE syndrome is a relatively common cause of deafness and blindness resulting from failure to form the primordia of specific organs due to deficient contribution of neural crest cell derivatives. The majority of CHARGE syndrome cases are caused by heterozygous mutations in CHD7 on chromosome 8q21. Those with CHARGE syndrome without CHD7 mutation typically do not have an identified genetic defect. 7q11.23 duplication syndrome is associated with mild facial dysmorphism, heart defects, language delay, and autism spectrum disorder. In the current literature, 7q11.23 duplication has not been associated with CHARGE syndrome, retinochoroidal colobomas, or significant ear abnormalities.Case presentationWe describe a patient with 7q11.23 duplication syndrome and clinical CHARGE syndrome with no variant in CHARGE-associated genes.ConclusionsThis case highlights the still incomplete understanding of the pathogenesis of CHARGE syndrome and raises the possibility of a dose-sensitive effect of genes in the 7q11.23 critical region on neural crest differentiation and fate.

A 6.3\xa0Mb maternally derived microduplication of 20p13p12.2 in a fetus with Brachydactyly type D and related literature review

BackgroundWith the introduction of genetic tests such as chromosomal microarray analysis (CMA) and exome sequencing (ES) into fetal medical practices, genotype–phenotype correlations in intrauterine-onset disorders have substantially improved. The BMP2 gene, located on the long arm of chromosome 20 plays a role in bone and cartilage development and is associated with Brachydactyly type A2, an autosomal dominant disease characterized by malformations of the middle phalanx of the index finger and abnormalities of the second toe. However, the BMP2 gene has so far never been reported as a candidate gene for Brachydactyly type D (BDD) affecting only the thumbs.Methods andresultsHere, we report one family possessing a maternally inherited 6.3 Mb microduplication of 20p13p12.2 including the BMP2 gene with discordant phenotypes between the mother and the fetus. The mother was affected with BDD alongside mild facial dysmorphism and learning difficulties, while the female fetus showed BDD, severe symmetric intrauterine growth restriction combined with oligohydramnios. The CMA and Trio ES tests were implemented. Trio ES ruled out other possible monogenic causes for the family. After reviewing cases and literature with duplications within this genomic region, we found that they are extremely rare and most of the cited cases were too small for comparison. The disturbance of the BMP2 gene could explain BDD, but the other clinical presentations in the mother and fetus are not yet fully understood.ConclusionThis study provides important evidence for the current understanding of genotype–phenotype association of this 6.3 Mb size duplication in the 20p13p12.2 region. This duplication is a unique CNV occurring so far only in this family. Further cases and research are needed to understand the discordance in the phenotypes between the mother and fetus and establish the relationship between BMP2 gene and BDD.

Oculodentodigital Dysplasia: A Cause of Hypomyelinating Leukodystrophy in Adults.

A middle-aged patient presented with mild facial dysmorphisms, small teeth with enamel hypoplasia, progressive gait disturbances, memory problems, and history of syndactyly, corrected in early childhood. MRI showed a hypomyelination pattern compatible with oculodentaldigital dysplasia (ODDD)1,2 (Figure 1). Ophthalmic findings revealed severe bilateral myopia. Exome sequencing revealed a heterozygous GJA1 missense variant ( p .Gly138Asp). The patient's mother (deceased) had developed slowly progressive neurodegeneration, ataxia, and seizures. MRI (age 80) revealed extensive leukodystrophic changes (Figure 2). ODDD diagnosis is often missed, highlighting the importance of clinical suspicion, MRI, and molecular testing in adult patients with facial, dental, and neurologic clinical features.

A novel de novo frameshift variation in the SON gene causing severe global developmental delay and seizures in a Chinese female.

With the rapid development of genetic detection technology, especially next-generation sequencing, identification of the aetiology of unexplained intellectual disabilities accompanied by seizures and other dysmorphic features has become possible. The purpose of our paper is to make a definitive diagnosis of a girl with neonatal hypotonia, severe global developmental delay, seizures and mild facial dysmorphism. The clinical data of the patient were retrospectively studied. Whole-exome sequencing was performed on a blood sample from the patient. Subsequently, Sanger sequencing was utilized for validation of variants and parental validation. The patient had hypotonia since the neonatal period. She showed a significant delay in physical and psychomotor development. She did not have any speech until the age of 2years and 6months. She had seizures that were easy to control with levetiracetam. The craniocerebral magnetic resonance imaging (MRI) then showed mild delayed myelination, enlarged bilateral ventricles and widened frontotemporal extracerebral space. Interictal video electroencephalogram (VEEG) was normal. She had esotropia and mild facial abnormalities with a flat nasal bridge and a short nose. She showed no abnormalities in the heart, genitourinary or skeletal systems. Whole-exome sequencing revealed a novel de novo variant c.5334_5335delAG (p. Arg1778Serfs*11) in the SON gene. Our paper reports a novel variant in the SON gene and provides a definitive diagnosis of a female with neonatal hypotonia, severe global developmental delay, seizures and mild facial abnormalities, which are symptoms consistent with Zhu-Tokita-Takenouchi-Kim syndrome (ZTTK syndrome).

A case of 7q21.3q31.1 deletion in a preterm boy with feeding intolerance and cyanotic episodes

This report describes a preterm male infant with phenotypic features of mild facial dysmorphism, congenital abnormalities of the hands and feet, corneal clouding, hypertonia, bilateral sensorineural hearing loss, and bilateral ventriculomegaly. His clinical course was significant for severe cyanotic episodes associated with the advancement of feed volume. Microarray analysis identified a large constitutional de novo deletion of 7q21.3q31.1. This rare deletion has never been reported in a preterm infant, and the management of this patient will help offer clinical guidance for this genetic condition.

Brain Calcifications in Complex Sexual Aneuploidy.

Brain Calcifications in Complex Sexual Aneuploidy.

Non-lethal Raine Syndrome Report Lacking Characteristic Clinical Features

Raine syndrome is a rare, often lethal autosomal recessive condition marked by congenital malformations that range in severity. Considering that several case reports of this syndrome describe cases of stillbirth or perinatal death, information about the clinical presentation and development of this condition in mild, non-lethal cases is lacking. With that in mind, in this case report, we describe the clinical, oro-dental, and skeletal findings of a 14-year-old Brazilian patient diagnosed with a mild form of non-lethal Raine syndrome. This patient has very mild facial dysmorphia, not displaying hypoplastic nose, micrognathia, low set ears or depressed nasal bridge, which is uncommon even in other mild, non-lethal cases of RS. Furthermore, this patient has bilateral brain calcifications and a series of oro-dental abnormalities, such as amelogenesis imperfecta and recurrent periodontal abcesses. Sanger sequencing of genomic DNA identified a homozygous missense variant c.1487C > T at exon 9 of FAM20C (NM_020223.4) in the patient. The patient's mother carries the same variant but is heterozygous. This variant predicts a proline to leucine substitution in position 496 (p.P496L, NP_064608.2) previously reported, which allows for the phenotypic comparison between these cases. This way, this case report calls attention to how differently RS can appear, highlighting the importance of new non-lethal Raine syndrome case reports to help further determine the phenotypic spectrum of this condition.