Molecular genetic screening of MBS1 locus on chromosome 13 for microdeletions and exclusion of FGF9, GSH1 and CDX2 as causative genes in patients with Moebius syndrome

Moebius syndrome is a rare disorder primarily characterized by congenital facial palsy, frequently accompanied by ocular abduction anomalies, and occasionally associated with orofacial, limb and musculoskeletal malformations. Abnormal development of cranial nerves V through XII underlines the disease pathogenesis. Although some investigations suggested that a causative gene may lie on 13q12.2–q13, there have been no molecular studies targeting possible microdeletions in this region to date. In the present study, we performed microdeletion analyses on 13q12.11–q13 in nine patients, and sequenced three candidate genes in nineteen patients for functional relevance and further resolution of our screening. We ruled out microdeletions on the critical region as a common cause of Moebius syndrome and excluded FGF9, GSH1 and CDX2 genes.     

Abnormal B.A.E.P. in a family with Moebius syndrome: evidence for supranuclear lesion

A family with Moebius syndrome is presented. Neurological lesions in the affected members are various: complete VI and VII cranial nerves palsy associated with mental retardation in the proband; left convergent strabismus and mental retardation in a brother of the proband and only mental retardation in a sister of the proband. The brainstem auditory evoked potentials (B. A.E.P.), investigated in the proband and his affected sister, are abnormal. The presence of the anomaly after the 3rd wave is consistent with a disfunction of the auditory tract at a supranuclear level. The mental deficiency and the supranuclear site of the acoustic lesion are an indication for a more general involvement of C.N.S. than cranial nerve nuclei alone.
Karyotype and dermatoglyphics of the three affected subjects were normal. The authors hypothesized the same disorganogenetic factor acting very early (4th-6th week of gestational age) on the metamerization process of limb buds mesoderm and brainstem gray matter.     

Autosomal recessive Noonan-like syndrome caused by homozygosity for a previously unreported variant in SPRED2

Noonan syndrome is characterized by variable phenotypic expressivity with characteristic dysmorphic facial features, varying degrees of intellectual disability, developmental delay, short stature, and congenital heart defects in 50–80%. Other findings include a webbed neck, cryptorchidism, coagulation defects and eye abnormalities.Thus far, Noonan syndrome has mainly been attributed to heterozygous pathogenic variants in 10+ different genes, with the rare exception of cases due to biallelic pathogenic variants in LZTR1. Recently, homozygous loss-of-function variants in SPRED2 have been identified as a cause of a recessive Noonan syndrome-like phenotype. We present the phenotypes of two additional patients with homozygosity for a previously unreported loss-of-function variant in SPRED2, thereby adding relevant clinical information about the recently described Noonan syndrome-like SPRED2-related phenotype.     

Will the real Moebius syndrome please stand up? A systematic review of the literature and statistical cluster analysis of clinical features

Moebius syndrome is a highly variable syndrome with abducens and facial nerve palsy as core features. Strict diagnostic criteria do not exist and the inconsistency of the associated features makes determination difficult. To determine what features are associated with Moebius syndrome we performed a systematic literature review resulting in a composite case series of 449 individuals labeled with Moebius syndrome. We applied minimum criteria (facial and abducens palsy) to determine the prevalence of associated clinical features in this series. Additionally, we performed statistical cluster analysis to determine which features tended to occur together. Our study comprises the largest series of patients with Moebius syndrome and the first to apply statistical methodology to elucidate clinical relationships. We present evidence for two groups within the Moebius diagnosis. Type 1: exhibiting micrognathia, limb anomalies and feeding/swallowing difficulty that tend to occur together. Type 2: phenotypically diverse but more associated with radiologically detectable neurologic abnormalities and developmental delay.     

Peripheral facial nerve communications and their clinical implications

The facial nerve (CN VII) nerve follows a torturous and complex path from its emergence at the pontomedullary junction to its various destinations. It exhibits a highly variable and complicated branching pattern and forms communications with several other cranial nerves. The facial nerve forms most of these neural intercommunications with branches of all three divisions of the trigeminal nerve (CN V), including branches of the auriculotemporal, buccal, mental, lingual, infraorbital, zygomatic, and ophthalmic nerves. Furthermore, CN VII also communicates with branches of the vestibulocochlear nerve (CN VIII), glossopharyngeal nerve (CN IX), and vagus nerve (CN X) as well as with branches of the cervical plexus such as the great auricular, greater, and lesser occipital, and transverse cervical nerves. This review intends to explore the many communications between the facial nerve and other nerves along its course from the brainstem to its peripheral branches on the human face. Such connections may have importance during clinical examination and surgical procedures of the facial nerve. Knowledge of the anatomy of these neural connections may be particularly important in facial reconstructive surgery, neck dissection, and various nerve transfer procedures as well as for understanding the pathophysiology of various cranial, skull base, and neck disorders.     

Rubinstein‐Taybi syndrome in Chinese population with four novel mutations

Rubinstein‐Taybi syndrome (RSTS, OMIM*180849) is a rare autosomal dominant disorder, characterized by distinctive facial features, short stature, broad and often angulated thumbs and halluces, with occasional congenital anomalies. Characteristic facial dysmorphic features include downslanting palpebral fissures, low hanging columella. RSTS is caused by pathogenic variants in two ubiquitously expressed and highly homologous genes, CREBBP (OMIM*600140) and EP300 (OMIM*600140). Clinical features were well reported especially in Caucasian ethnicity. We would like to report the clinical phenotype of RSTS in our Chinese population and highlight four novel mutations in CREBBP gene.     

Clinical and molecular spectrum of Wiedemann-Steiner syndrome,an emerging member of the chromatinopathy family

Wiedemann-Steiner syndrome (OMIM #605130) is a rare congenital malformation syndrome characterized by hypertrichosis cubiti associated with short stature; consistent facial features, including long eyelashes, thick or arched eyebrows with a lateral flare, wide nasal bridge, and downslanting and vertically narrow palpebral fissures; mild to moderate intellectual disability; behavioral difficulties; and hypertrichosis on the back. It is caused by heterozygous pathogenic variants in KMT2A. This gene has an established role in histone methylation, which explains the overlap of Wiedemann-Steiner syndrome with other chromatinopathies, a heterogeneous group of syndromic conditions that share a common trigger: The disruption of one of the genes involved in chromatin modification, leading to dysfunction of the epigenetic machinery.     

Two SOX11 variants cause Coffin–Siris syndrome with a new feature of sensorineural hearing loss

Coffin-Siris syndrome (CSS, OMIM#135900) is a rare congenital disorder associated with neurodevelopmental and dysmorphic features. The primary cause of CSS is pathogenic variants in any of 9 BAF chromatin-remodeling complex encoding genes or the genes SOX11 and PHF6. Herein, we performed whole-exome sequencing (WES) and a series of analyses of growth-related, auditory, and radiological findings in two probands with syndromic sensorineural hearing loss and inner ear malformations who exhibited distinctive facial features, intellectual disability, growth retardation, and fifth finger malformation. Two de novo variants in the SOX11 gene (c.148A>C:p.Lys50Asn; c.811_814del:p.Asn271Serfs*10) were detected in these probands and were identified as pathogenic variants as per ACMG guidelines. These probands were diagnosed as having CSS based upon clinical and genetic findings. This is the first report of CSS caused by variants in SOX11 gene in Chinese individuals. Deleterious SOX11 variants can result in sensorineural hearing loss with inner ear malformation, potentially extending the array of phenotypes associated with these pathogenic variants. We suggest that both genetic and clinical findings be considered when diagnosing syndromic hearing loss.     

Oral–facial–digital syndrome type VI (Váradi syndrome): Further clinical delineation

Cerebellar anomalies are consistent findings in patients with the oral–facial–digital syndrome type VI (Váradi syndrome) in addition to variable facial and oral changes, and polysyndactyly of hands and feet. We report 3 unrelated patients with this entity who have a hypoplastic cerebellar vermis shown by magnetic resonance imaging (MRI), as well as clinical signs of cerebellar defect. Polydactyly of the hands is characterized by a central Y-shaped metacarpal. Clinically recurrent episodes of tachypnea and hyperpnea are remarkable. Postnatal growth is delayed with short stature in all 3 patients possibly due to growth hormone deficiency in one of them. In contrast to reported patients who are all severely mentally retarded, one of our patients is of normal intelligence. Type VI oral-facial-digital syndrome is an autosomal-recessive trait and may be detected prenatally.     

A new patella syndrome

A 14-year-old boy is reported with bilateral hypoplastic patellae and multiple congenital skeletal anomalies. Since this constellation of bony malformations has not been described previously, we believe this represents a new syndrome most probably of genetic etiology.     

Refining the Primrose syndrome phenotype: A study of five patients with ZBTB20 de novo variants and a review of the literature

Primrose syndrome is a rare autosomal dominant condition caused by heterozygous missense variants within ZBTB20. Through an exome sequencing approach (as part of the Deciphering Developmental Disorders [DDD] study) we have identified five unrelated individuals with previously unreported, de novo ZBTB20 pathogenic missense variants. All five missense variants targeted the C2H2 zinc finger domains. This genotype‐up approach has allowed further refinement of the Primrose syndrome phenotype. Major characteristics (>90% individuals) include an intellectual disability (most frequently in the moderate range), a recognizable facial appearance and brain MRI abnormalities, particularly abnormalities of the corpus callosum. Other frequent clinical associations (in 50–90% individuals) include sensorineural hearing loss (83%), hypotonia (78%), cryptorchidism in males (75%), macrocephaly (72%), behavioral issues (56%), and dysplastic/hypoplastic nails (57%). Based upon these clinical data we discuss our current management of patients with Primrose syndrome.     

Genetic and clinical findings in a Chinese cohort of patients with collagen VI‐related myopathies

Collagen VI‐related myopathy, caused by pathogenic variants in the genes encoding collagen VI, represents a clinical continuum from Ullrich congenital muscular dystrophy (UCMD) to Bethlem myopathy (BM). Clinical data of 60 probands and their family members were collected and muscle biopsies of 26 patients were analyzed. COL6A1, COL6A2 and COL6A3 exons were analyzed by direct sequencing or next generation sequencing (NGS). Sixty patients were characterized by delayed motor milestones, muscle weakness, skin and joint changes with 40 UCMD and 20 BM. Muscle with biopsies revealed dystrophic changes and showed completely deficiency of collagen VI or sarcolemma specific collagen VI deficiency. We identified 62 different pathogenic variants in these 60 patients, with 34 were first reported while 28 were previously known; 72 allelic pathogenic variants in COL6A1 (25/72, 34.7%), COL6A2 (33/72, 45.8%) and COL6A3 (14/72, 19.4%). We also found somatic mosaic variant in the parent of 1 proband by personal genome machine amplicon deep sequencing for mosaicism. Here we provide clinical, histological and genetic evidence of collagen VI‐related myopathy in 60 Chinese patients. NGS is a valuable approach for diagnosis and accurate diagnosis provides useful information for genetic counseling of related families.     

A case of severe TBCE‐negative hypoparathyroidism‐retardation‐dysmorphism syndrome: Case report and literature review

Hypoparathyroidism‐retardation‐dysmorphism syndrome (HRD) is a rare autosomal recessive disorder attributed to the mutations in the tubulin‐specific chaperone E (TBCE) gene, which is vital for microtubule function during mitosis, organelle positioning, and neuronal cytokinesis. HRD is a congenital syndromic hypoparathyroidism associated with growth deficiency, microcephaly, intellectual disability, ocular anomalies, and facial dysmorphism. To our knowledge, there is only one published case of mild HRD‐like syndrome with no identifiable genetic etiology. We report a case of severe TBCE‐negative phenotypic HRD in a 4‐year‐old female from India presenting with hypocalcemic seizures due to congenital hypoparathyroidism, extreme microcephaly, growth deficiency, ocular anomalies, and facial dysmorphism. SNP microarray and whole exome sequencing (WES) did not detect any abnormalities in TBCE or other genes of interest. WES revealed two variants of unknown clinical significance in CASC5 gene, which codes for a protein in the kinetochore and, interestingly similar to TBCE, is essential for proper microtubule function during mitosis and cell proliferation and has been implicated in primary microcephaly disorders. However, further targeted sequencing in the parents revealed both variants inherited from the unaffected mother. Significant copy number variant noise in the proband and her parents limited further analysis. At this time the role of variants in the CASC5 gene is unclear and cannot explain our patient's phenotype. In conclusion, we report a severe case of phenotypic HRD syndrome, in which extensive genetic evaluation failed to reveal an etiology. Our case demonstrates that the pathogenesis of HRD may be genetically heterogenous, meriting further genetic investigations.     

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.     

Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients

Noonan syndrome (NS) is a common autosomal dominant/recessive disorder. No large-scale study has been conducted on NS in China, which is the most populous country in the world. Next-generation sequencing (NGS) was used to identify pathogenic variants in patients that exhibited NS-related phenotypes. We assessed the facial features and clinical manifestations of patients with pathogenic or likely pathogenic variants in the RAS-MAPK signaling pathway. Gene-related Chinese NS facial features were described using artificial intelligence (AI).NGS identified pathogenic variants in 103 Chinese patients in eight NS-related genes: PTPN11 (48.5%), SOS1 (12.6%), SHOC2 (11.7%), KRAS (9.71%), RAF1 (7.77%), RIT1 (6.8%), CBL (0.97%), NRAS (0.97%), and LZTR1 (0.97%). Gene-related facial representations showed that each gene was associated with different facial details. Eight novel pathogenic variants were detected and clinical features because of specific genetic variants were reported, including hearing loss, cancer risk due to a PTPN11 pathogenic variant, and ubiquitous abnormal intracranial structure due to SHOC2 pathogenic variants. NGS facilitates the diagnosis of NS, especially for patients with mild/moderate and atypical symptoms. Our study describes the genotypic and phenotypic spectra of NS in China, providing new insights into distinctive clinical features due to specific pathogenic variants.     

两例父源性17q12微缺失综合征胎儿的产前诊断和遗传学分析

目的:探讨两例父源性17q12微缺失综合征胎儿的产前诊断和遗传咨询。方法:一名孕妇的两例胎儿的孕中晚期超声检查均提示肾脏异常和羊水过多,应用单核苷酸多态性分析(single nucleotide polymorphism array,SNP-array)分别对第1胎的脐血样本和第2胎的羊水样本进行产前诊断。发现第1胎染...     

Ipsilateral foot and contralateral hand anomalies in a patient with Poland-Moebius syndrome

This report describes a patient who had bilateral facial nerve paralysis, external ophthalmoplegia, absence of pectoralis major muscle at right side, ipsilateral hand and foot, and contralateral hand anomalies. To our knowledge, this is the first patient with Poland syndrome reported in combination with Moebius syndrome, presenting with contralateral hand and ipsilateral foot anomalies.     

Moebius syndrome in a child and extremity defect in her father

A child with Moebius syndrome and minor extremity anomalies is described. Her father had a transverse defect of the right arm with absence of the radius and ulna just below the elbow but no cranial nerve dysfunction. While possibly unrelated, review of the literature suggests these anomalies may both be part of a single broad spectrum syndrome, perhaps dominantly inherited.     

Discovering a new part of the phenotypic spectrum of Coffin-Siris syndrome in a fetal cohort

PurposeGenome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally identified variants can be challenging and is hampered by our often limited knowledge of prenatal phenotypes. To better delineate the prenatal phenotype of Coffin-Siris syndrome (CSS), we collected clinical data from patients with a prenatal phenotype and a pathogenic variant in one of the CSS-associated genes.MethodsClinical data was collected through an extensive web-based survey.ResultsWe included 44 patients with a variant in a CSS-associated gene and a prenatal phenotype; 9 of these patients have been reported before. Prenatal anomalies that were frequently observed in our cohort include hydrocephalus, agenesis of the corpus callosum, hypoplastic left heart syndrome, persistent left vena cava, diaphragmatic hernia, renal agenesis, and intrauterine growth restriction. Anal anomalies were frequently identified after birth in patients with ARID1A variants (6/14, 43%). Interestingly, pathogenic ARID1A variants were much more frequently identified in the current prenatal cohort (16/44, 36%) than in postnatal CSS cohorts (5%-9%).ConclusionOur data shed new light on the prenatal phenotype of patients with pathogenic variants in CSS genes.     

Differentiating molecular etiologies of Angelman syndrome through facial phenotyping using deep learning

Angelman syndrome (AS) is caused by several genetic mechanisms that impair the expression of maternally‐inherited UBE3A through deletions, paternal uniparental disomy (UPD), UBE3A pathogenic variants, or imprinting defects. Current methods of differentiating the etiology require molecular testing, which is sometimes difficult to obtain. Recently, computer‐based facial analysis systems have been used to assist in identifying genetic conditions based on facial phenotypes. We sought to understand if the facial‐recognition system DeepGestalt could find differences in phenotype between molecular subtypes of AS. Images and molecular data on 261 individuals with AS ranging from 10 months through 32 years were analyzed by DeepGestalt in a cross‐validation model with receiver operating characteristic (ROC) curves generated. The area under the curve (AUC) of the ROC for each molecular subtype was compared and ranked from least to greatest differentiable phenotype. We determined that DeepGestalt demonstrated a high degree of discrimination between the deletion subtype and UPD or imprinting defects, and a lower degree of discrimination with the UBE3A pathogenic variants subtype. Our findings suggest that DeepGestalt can recognize subclinical differences in phenotype based on etiology and may provide decision support for testing.