An interactive atlas of three-dimensional syndromic facial morphology.

Craniofacial phenotyping is critical for both syndrome delineation and diagnosis because craniofacial abnormalities occur in 30% of characterized genetic syndromes. Clinical reports, textbooks, and available software tools typically provide two-dimensional, static images and illustrations of the characteristic phenotypes of genetic syndromes. In this work, we provide an interactive web application that provides three-dimensional, dynamic visualizations for the characteristic craniofacial effects of 95 syndromes. Users can visualize syndrome facial appearance estimates quantified from data and easily compare craniofacial phenotypes of different syndromes. Our application also provides a map of morphological similarity between a target syndrome and other syndromes. Finally, users can upload 3D facial scans of individuals and compare them to our syndrome atlas estimates. In summary, we provide an interactive reference for the craniofacial phenotypes of syndromes that allows for precise, individual-specific comparisons of dysmorphology.

Loss-of-function of kinesin-5 KIF11 causes microcephaly, chorioretinopathy, and developmental disorders through chromosome instability and cell cycle arrest.

Kinesin motors play a fundamental role in development by controlling intracellular transport, spindle assembly, and microtubule organization. In humans, patients carrying mutations in KIF11 suffer from an autosomal dominant inheritable disease called microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR). While mitotic functions of KIF11 proteins have been well documented in centrosome separation and spindle assembly, cellular mechanisms underlying KIF11 dysfunction and MCLMR remain unclear. In this study, we generate KIF11-inhibition chick and zebrafish models and find that KIF11 inhibition results in microcephaly, chorioretinopathy, and severe developmental defects in vivo. Notably, loss-of-function of KIF11 causes the formation of monopolar spindle and chromosome misalignment, which finally contribute to cell cycle arrest, chromosome instability, and cell death. Our results demonstrate that KIF11 is crucial for spindle assembly, chromosome alignment, and cell cycle progression of progenitor stem cells, indicating a potential link between polyploidy and MCLMR. Our data have revealed that KIF11 inhibition cause microcephaly, chorioretinopathy, and development disorders through the formation of monopolar spindle, polyploid, and cell cycle arrest.

Subcellular localisation of truncated MAGEL2 proteins: insight into the molecular pathology of Schaaf-Yang syndrome.

Schaaf-Yang syndrome (SYS) is an ultra-rare neurodevelopmental disorder caused by truncating mutations in MAGEL2 Heterologous expression of wild-type (WT) or a truncated (p.Gln638*) C-terminal HA-tagged MAGEL2 revealed a shift from a primarily cytoplasmic to a more nuclear localisation for the truncated protein variant. We now extend this analysis to six additional SYS mutations on a N-terminal FLAG-tagged MAGEL2. Our results replicate and extend our previous findings, showing that all the truncated MAGEL2 proteins consistently display a predominant nuclear localisation, irrespective of the C-terminal or N-terminal position and the chemistry of the tag. The variants associated with arthrogryposis multiplex congenita display a more pronounced nuclear retention phenotype, suggesting a correlation between clinical severity and the degree of nuclear mislocalisation. These results point to a neomorphic effect of truncated MAGEL2, which might contribute to the pathogenesis of SYS.

Olfactory bulb anomalies in KBG syndrome mouse model and patients.

ANKRD11 (ankyrin repeat domain 11) is a chromatin regulator and the only gene associated with KBG syndrome, a rare neurodevelopmental disorder. We have previously shown that Ankrd11 regulates murine embryonic cortical neurogenesis. Here, we show a novel olfactory bulb phenotype in a KBG syndrome mouse model and two diagnosed patients. Conditional knockout of Ankrd11 in murine embryonic neural stem cells leads to aberrant postnatal olfactory bulb development and reduced size due to reduction of the olfactory bulb granule cell layer. We further show that the rostral migratory stream has incomplete migration of neuroblasts, reduced cell proliferation as well as aberrant differentiation of neurons. This leads to reduced neuroblasts and neurons in the olfactory bulb granule cell layer. In vitro, Ankrd11-deficient neural stem cells from the postnatal subventricular zone display reduced migration, proliferation, and neurogenesis. Finally, we describe two clinically and molecularly confirmed KBG syndrome patients with anosmia and olfactory bulb and groove hypo-dysgenesis/agenesis. Our report provides evidence that Ankrd11 is a novel regulator of olfactory bulb development and neuroblast migration. Moreover, our study highlights a novel clinical sign of KBG syndrome linked to ANKRD11 perturbations in mice and humans.

Natural history of adults with KBG syndrome: A physician-reported experience.

PURPOSE: KBG syndrome (KBGS) is a rare neurodevelopmental syndrome caused by haploinsufficiency of ANKRD11. The childhood phenotype is extensively reported but limited for adults. Thus, we aimed to delineate the clinical features of KBGS. METHODS: We collected physician-reported data of adults with molecularly confirmed KBGS through an international collaboration. Moreover, we undertook a systematic literature review to determine the scope of previously reported data. RESULTS: The international collaboration identified 36 adults from 31 unrelated families with KBGS. Symptoms included mild/borderline intellectual disability (n = 22); gross and/or fine motor difficulties (n = 15); psychiatric and behavioral comorbidities including aggression, anxiety, reduced attention span, and autistic features (n = 26); nonverbal (n = 3), seizures with various seizure types and treatment responses (n = 10); ophthalmological comorbidities (n = 20). Cognitive regression during adulthood was reported once. Infrequent features included dilatation of the ascending aorta (n = 2) and autoimmune conditions (n = 4). Education, work, and residence varied, and the diversity of professional and personal roles highlighted the range of abilities seen. The literature review identified 154 adults reported across the literature, and we have summarized the features across both data sets. CONCLUSION: Our study sheds light on the long-term neurodevelopmental outcomes, seizures, behavioral and psychiatric features, and education, work, and living arrangements for adults with KBGS.

ASXL3-related disorder: Molecular phenotyping and comprehensive review providing insights into disease mechanism.

ASXL3-related disorder, sometimes referred to as Bainbridge-Ropers syndrome, was first identified as a distinct neurodevelopmental disorder by Bainbridge et al. in 2013. Since then, there have been a number of case series and single case reports published worldwide. A comprehensive review of the literature was carried out. Abstracts were screened, relevant literature was analysed, and descriptions of common phenotypic features were quantified. ASXL3 variants were collated and categorised. Common phenotypic features comprised global developmental delay or intellectual disability (97%), feeding problems (76%), hypotonia (88%) and characteristic facial features (93%). The majority of genetic variants were de novo truncating variants in exon 11 or 12 of the ASXL3 gene. Several gaps in our knowledge of this disorder were identified, namely, underlying pathophysiology and disease mechanism, disease contribution of missense variants, relevance of variant location, prevalence and penetrance data. Clinical information is currently limited by patient numbers and lack of longitudinal data, which this review aims to address.

Pathogenic variants in SOX11 mimicking Pitt-Hopkins syndrome phenotype.

Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder characterised by severe intellectual disability (ID), distinctive facial features and autonomic nervous system dysfunction, caused by TCF4 haploinsufficiency. We clinically diagnosed with PTHS a 14 6/12 -year-old female, who had a normal status of TCF4. The pathogenic c.667del (p.Asp223MetfsTer45) variant in SOX11 was identified through whole exome sequencing (WES). SOX11 variants were initially reported to cause Coffin-Siris syndrome (CSS), characterised by growth restriction, moderate ID, coarse face, hypertrichosis and hypoplastic nails. However, recent studies have provided evidence that they give rise to a distinct neurodevelopmental disorder. To date, SOX11 variants are associated with a variable phenotype, which has been described to resemble CSS in some cases, but never PTHS. By reviewing both clinically and genetically 32 out of 82 subjects reported in the literature with SOX11 variants, for whom detailed information are provided, we found that 7/32 (22%) had a clinical presentation overlapping PTHS. Furthermore, we made a confirmation that overall SOX11 abnormalities feature a distinctive disorder characterised by severe ID, high incidence of microcephaly and low frequency of congenital malformations. Purpose of the present report is to enhance the role of clinical genetics in assessing the individual diagnosis after WES results.

Cerebellar Heterotopia: Broadening the Neuroradiological Spectrum of KBG Syndrome.

KBG syndrome is a rare genetic disorder caused by heterozygous pathogenic variants in ANKRD11. Affected individuals have developmental delay, short stature, characteristic facial features, and other dysmorphic findings. To date, a spectrum of unspecific neuroradiological defects has been reported in KBG patients, such as cortical defects, white matter abnormalities, corpus callosum, and cerebellar vermis hypoplasia.Deep clinical and neuroradiological phenotyping and genotype of a patient presenting with mild cognitive and behavioral problems were obtained after written informed consent.We herein describe the first KBG patient presenting with cerebellar heterotopia, a heterogeneous malformation characterized by the presence of clusters of neurons within the white matter of cerebellar hemispheres.This novel association broadens the neuroradiological spectrum of KBG syndrome, and further prompts to investigate the potential functions of ANKRD11 in cerebellar development.

A severe neurocognitive phenotype caused by biallelic CHD3 variants in two siblings.

CHD3 heterozygous variants are associated with Snijders Blok-Campeau syndrome (SBCS) which consists of intellectual disability (ID), macrocephaly, and dysmorphic facies. Most reported variants are missense or loss of function clustered within the ATPase/helicase domain of the protein. We report a severe neurocognitive phenotype caused by biallelic CHD3 variants in two siblings, each inherited from a mildly affected parent. Male and female siblings were referred to the Genetics Clinic due to severe ID and profound dysmorphism. The parents are first cousins of Iranian descent with borderline intellectual abilities. Exome sequencing was performed for the affected female and her parents. A single homozygous candidate variant in the CHD3 gene was detected in the proband: c.5384_5389dup. p.Arg1796_Phe1797insTrpArg, resulting in an in-frame insertion of 2 amino acids located outside the ATPase/helicase domain at the C-terminal region of CHD3-encoding residues. This variant is classified as likely pathogenic according to ACMG guidelines. The variant was detected in a heterozygous state in each parent. Both affected siblings were homozygous, while their unaffected brother did not carry the variant. Biallelic CHD3 variants cause a severe neurodevelopmental syndrome that is distinguishable from SBCS. We assume that the variant type (in-frame insertion) and location may enable CHD3 biallelic variants.

RNA analysis and computer-aided facial phenotyping help to classify a novel TRIO splice site variant.

Pathogenic variants in TRIO, encoding the guanine nucleotide exchange factor, are associated with two distinct neurodevelopmental delay phenotypes: gain-of-function missense mutations within the spectrin repeats are causative for a severe developmental delay with macrocephaly (MIM: 618825), whereas loss-of-function missense variants in the GEF1 domain and truncating variants throughout the gene lead to a milder developmental delay and microcephaly (MIM: 617061). In three affected family members with mild intellectual disability/NDD and microcephaly, we detected a novel heterozygous TRIO variant at the last coding base of exon 31 (NM_007118.4:c.4716G>A). RNA analysis from patient-derived lymphoblastoid cells confirmed aberrant splicing resulting in the skipping of exon 31 (r.4615_4716del), leading to an in-frame deletion in the first Pleckstrin homology subdomain of the GEF1 domain: p.(Thr1539_Lys1572del). To test for a distinct gestalt, facial characteristics of the family members and 41 previously published TRIO cases were systematically evaluated via GestaltMatcher. Computational analysis of the facial gestalt suggests a distinguishable facial TRIO-phenotype not outlined in the existing literature.

Novel Alu insertion in the ZEB2 gene causing Mowat-Wilson syndrome.

Alu elements are short, interspersed elements located throughout the genome, playing a role in human diversity, and occasionally causing genetic diseases. Here, we report a novel Alu insertion causing Mowat-Wilson syndrome, a rare neurodevelopmental disorder, in an 8-year-old boy displaying the typical clinical features for Mowat-Wilson syndrome. The variant was not initially detected in genome sequencing data, but through deep phenotyping, which pointed to only one plausible candidate gene, manual inspection of genome sequencing alignment data enabled us to identify a de novo heterozygous Alu insertion in exon 8 of the ZEB2 gene. Nanopore long-read sequencing confirmed the Alu insertion, leading to the formation of a premature stop codon and likely haploinsufficiency of ZEB2. This underscores the importance of deep phenotyping and mobile element insertion analysis in uncovering genetic causes of monogenic disorders as these elements might be overlooked in standard next-generation sequencing protocols.

Expanding the phenotypic and genotypic characteristics of trichohepatoenteric syndrome: a report of eight patients from five unrelated families.

BACKGROUND: Trichohepatoenteric syndrome (THES) is characterized by neonatal-onset intractable diarrhea. It often requires long-term total parenteral nutrition (TPN). In addition, other characteristic findings of the syndrome include growth retardation, facial dysmorphism, hair abnormalities, various immunological problems and other rare system findings. Two genes and their associated pathogenic variants have been associated with this syndrome: SKIC3 and SKIC2. METHODS AND RESULTS: In this case series, the clinical findings and molecular analysis results of a total of 8 patients from 5 different families who presented with persistent diarrhea and were diagnosed with THES were shared. Pathogenic variants were detected in the SKIC3 gene in 6 of our patients and in the SKIC2 gene in 2 patients. It was planned to compare the clinical findings of our patients with other patients, together with literature data, and to present yet-undefined phenotypic features that may be related to THES. In our case series, in addition to our patients with a novel variant, patient number 2 had a dual phenotype (THES and Spondyloepimetaphyseal dysplasia, sponastrime type) that has not been reported yet. Delay in gross motor skills, mild cognitive impairment, radioulnar synostosis, osteoporosis, nephropathy and cystic lesions (renal and liver) were observed as unreported phenotypic findings. CONCLUSIONS: We are expanding the clinical and molecular repertoire of the syndrome regarding patients diagnosed with THES. We recommend that the NGS (next-generation sequencing) multigene panel should be used as a diagnostic tool in cases with persistent diarrhea.

Caudal regression in fetus with de novo SMARCA2 pathogenic variant.

Nicolaides-Baraitser syndrome (NCBRS) is a rare autosomal dominant genetic condition that is characterized by severe intellectual disability, dysmorphic facial features, short stature, sparse hair, and early onset seizures. This diagnosis is established by suggestive clinical findings and the identification of a heterozygous SMARCA2 pathogenic variant by molecular genetic testing. There are not, however, consensus clinical diagnostic criteria for this condition as there are so few documented cases. Here, we present a case of prenatally diagnosed caudal regression with sacral agenesis and congenital vertical talus (rocker bottom feet) that was ultimately found to have a de novo SMARCA2 pathogenic variant. The patient had an amniocentesis with normal karyotype and microarray followed by failed direct rapid whole exome sequencing (WES) due to maternal cell contamination. She elected for termination of the pregnancy based on the clinical prognosis of the ultrasound findings; WES revealed a pathogenic variant after her termination. We believe this is the first case of these findings associated with NCBRS. If any future cases of either finding are found in association with a SMARCA2 genetic variant, caudal regression and rocker bottom feet should be included in the spectrum of physical traits associated with this pathogenic variant.

An adolescent case of ASXL3-related disorder with delayed onset of feeding difficulty.

BACKGROUND: ASXL3-related disorder, first described in 2013, is a genetic disorder with an autosomal dominant inheritance that is caused by a heterozygous loss-of-function variant in ASXL3. The most characteristic feature is neurodevelopmental delay with consistently limited speech. Feeding difficulty is a main symptom observed in infancy. However, no adolescent case has been reported. CASE PRESENTATION: A 14-year-old girl with ASXL3-related syndrome was referred to our hospital with subacute onset of emotional lability. Limbic encephalitis was ruled out by examination; however, the patient gradually showed a lack of interest in eating, with decreased diet volume. Consequently, she experienced significant weight loss. She experienced no symptoms of bulimia, or food allergy; therefore, avoidant/restrictive food intake disorder (ARFID) was clinically suspected. CONCLUSIONS: We reported the first case of ASXL3-related disorder with adolescent onset of feeding difficulty. ARFID was considered a cause of the feeding difficulty.

Trichohepatoenteric syndrome type 1: expanding the clinical spectrum of THES type 1 due to a homozygous variant in the SKIC3 gene.

Trichohepatoenteric syndrome (THES), also known as phenotypic diarrhea or syndromic diarrhea, is a rare autosomal recessive genetic disorder caused by mutations in SKIC2 (THES-type 2) or SKIC3 (THES-type 1) and is characterized by early onset diarrhea, woolly brittle hair, facial dysmorphic features and liver disease. We report the case of a 24-month-old girl who presented with chronic diarrhea since the neonatal period along with intrauterine growth restriction (IUGR), developmental delay, dysmorphic features, congenital heart defects, liver disease, and recurrent infections. The diagnosis was made through whole-exome sequencing analysis, which detected a homozygous variant (c.4070del, p.Pro1357Leufs*10) in the SKIC3 gene. The patient required parenteral nutrition and was hospitalized for the first 10 months of life and then discharged on PN after showing improvement. She remained stable on PN after discharge despite a few admissions for central line infections. Recent follow-up at the age of 2 years revealed that she was stable on long-term parenteral nutrition and that she had advanced chronic liver disease.

Dermatological manifestations in Costello syndrome: A prospective multicentric study of 31 HRAS-positive variant patients.

BACKGROUND: Data on dermatological manifestations of Costello syndrome (CS) remain heterogeneous and lack in validated description. OBJECTIVES: To describe the dermatological manifestations of CS; compare them with the literature findings; assess those discriminating CS from other RASopathies, including cardiofaciocutaneous syndrome (CFCS) and the main types of Noonan syndrome (NS); and test for dermatological phenotype-genotype correlations. METHODS: We performed a 10-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Thirty-one patients were enrolled. Hair abnormalities were ubiquitous, including wavy or curly hair and excessive eyebrows, respectively in 68% and 56%. Acral excessive skin (AES), papillomas and keratotic papules (PKP), acanthosis nigricans (AN), palmoplantar hyperkeratosis (PPHK) and 'cobblestone' papillomatous papules of the upper lip (CPPUL), were noted respectively in 84%, 61%, 65%, 55% and 32%. Excessive eyebrows, PKP, AN, CCPUL and AES best differentiated CS from CFCS and NS. Multiple melanocytic naevi (>50) may constitute a new marker of attenuated CS associated with intragenic duplication in HRAS. Oral acitretin may be highly beneficial for therapeutic management of PPHK. No significant dermatological phenotype-genotype correlation was determined between patients with and without HRAS c.34G>A (p.G12S). CONCLUSIONS AND RELEVANCE: This validated phenotypic characterization of a large number of patients with CS will allow future researchers to make a positive diagnosis, and to differentiate CS from CFCS and NS.

Complex Craniosynostosis in Pitt-Hopkins Syndrome: Case Report in Twins.

INTRODUCTION: Pitt-Hopkins syndrome (PTHS) is a rare genetic syndrome associated with neurodevelopmental disorders and craniofacial dysmorphisms caused by variations in the TCF4 transition factor. The aim of this article was to report the case of two twin infants diagnosed with PTHS, confirmed by the identification of a heterozygous pathogenic variant in the TCF4 gene through DNA extracted from a buccal swab. CASE PRESENTATION: Both infants presented with craniofacial asymmetry with a metopic crest and cranial deformity. During the diagnostic investigation, computed tomography with three-dimensional reconstruction of the skull showed premature fusion of the left coronal and metopic sutures in both twins. They underwent craniofacial reconstruction at the 9th month of age using a combination of techniques. The postoperative outcomes were satisfactory in both cases. CONCLUSION: To the best of our knowledge, this is the first case report to describe the occurrence of complex craniosynostosis (CCS) in children with PTHS. Further studies are needed to determine whether the co-occurrence of PTHS and CCS described here indicates an association or is explained by chance.

Mowat-Wilson Syndrome: Case Report and Review of ZEB2 Gene Variant Types, Protein Defects and Molecular Interactions.

Mowat-Wilson syndrome (MWS) is a rare genetic neurodevelopmental congenital disorder associated with various defects of the zinc finger E-box binding homeobox 2 (ZEB2) gene. The ZEB2 gene is autosomal dominant and encodes six protein domains including the SMAD-binding protein, which functions as a transcriptional corepressor involved in the conversion of neuroepithelial cells in early brain development and as a mediator of trophoblast differentiation. This review summarizes reported ZEB2 gene variants, their types, and frequencies among the 10 exons of ZEB2. Additionally, we summarized their corresponding encoded protein defects including the most common variant, c.2083 C>T in exon 8, which directly impacts the homeodomain (HD) protein domain. This single defect was found in 11% of the 298 reported patients with MWS. This review demonstrates that exon 8 encodes at least three of the six protein domains and accounts for 66% (198/298) of the variants identified. More than 90% of the defects were due to nonsense or frameshift changes. We show examples of protein modeling changes that occurred as a result of ZEB2 gene defects. We also report a novel pathogenic variant in exon 8 in a 5-year-old female proband with MWS. This review further explores other genes predicted to be interacting with the ZEB2 gene and their predicted gene-gene molecular interactions with protein binding effects on embryonic multi-system development such as craniofacial, spine, brain, kidney, cardiovascular, and hematopoiesis.

The Pivotal Role of Oxytocin's Mechanism of Thermoregulation in Prader-Willi Syndrome, Schaaf-Yang Syndrome, and Autism Spectrum Disorder.

Oxytocin (Oxt) regulates thermogenesis, and altered thermoregulation results in Prader-Willi syndrome (PWS), Schaaf-Yang syndrome (SYS), and Autism spectrum disorder (ASD). PWS is a genetic disorder caused by the deletion of the paternal allele of 15q11-q13, the maternal uniparental disomy of chromosome 15, or defects in the imprinting center of chromosome 15. PWS is characterized by hyperphagia, obesity, low skeletal muscle tone, and autism spectrum disorder (ASD). Oxt also increases muscle tonicity and decreases proteolysis while PWS infants are hypotonic and require assisted feeding in early infancy. This evidence inspired us to merge the results of almost 20 years of studies and formulate a new hypothesis according to which the disruption of Oxt's mechanism of thermoregulation manifests in PWS, SYS, and ASD through thermosensory abnormalities and skeletal muscle tone. This review will integrate the current literature with new updates on PWS, SYS, and ASD and the recent discoveries on Oxt's regulation of thermogenesis to advance the knowledge on these diseases.

[Analysis of genetic etiology in a patient with 1p36 deletion syndrome in conjunct with Snijders Blok-Campeau syndrome].

OBJECTIVE: To explore the genetic basis for a patient with unexplained developmental delay and special facial features. METHODS: A male patient admitted to the Maternal and Child Health Care Hospital of Gansu Province on May 27, 2021 due to infertility was selected as the study subject. Clinical data of the patient was collected, and genomic DNA was extracted from peripheral blood samples from the patient and his parents. Whole exome sequencing (WES) was carried out, and candidate variant was verified by Sanger sequencing. RESULTS: The patient was found to harbor a 2.54 Mb deletion in 1p36.33p36.32 and a heterozygous c.1123G>C (p.E375Q) variant of the CHD3 gene, neither of which was detected in his parents. CONCLUSION: The patient was diagnosed with Snijders Blok-Campeau syndrome in conjunct with 1p36 deletion syndrome, which has enabled genetic counseling for his family.