P35S mutation in the NOG gene associated with Teunissen-Cremers syndrome and features of multiple NOG joint-fusion syndromes

We report on a new family with Teunissen-Cremers syndrome. The proband presented with congenital conductive hearing loss due to stapes ankylosis and incus short process fixation with skeletal anomalies including symphalangism, broad thumbs and broad first toes, syndactyly, brachydactyly, contractures of the elbows and knees, hyperopia and lens opacities. This constellation of symptoms is compatible with the diagnosis of one of the joint-fusion syndromes namely the Teunissen-Cremers syndrome (TCS), which was first reported in 1990. Mutations in the NOG gene which encodes the noggin protein, a bone morphogenetic protein antagonist, have been identified in TCS as well as in four other autosomal dominant disorders including proximal symphalangism (SYM1), multiple synostosis (SYNS1), Tarsal-Carpal coalition syndrome and brachydactyly type B (BDB). Interestingly, we found that the mutation P35S described in this family has already been reported in patients affected with SYM1 as well as with BDB syndromes.     

Esophageal atresia/tracheoesophageal fistula and proximal symphalangism in a patient with a NOG nonsense mutation

Esophageal atresia and tracheoesophageal fistula (EA/TEF) are relatively common malformations of the human foregut. The etiology remains incompletely understood with genetic causes identified in a small minority of affected patients. We present the case of a newborn with type C EA/TEF along with proximal symphalangism found to have a de novo NOG nonsense mutation. Patients with chromosome 17q deletions including the NOG gene have previously been reported to have EA/TEF but mutations in the gene have not been identified in patients with this malformation. This case provides evidence that haploinsufficiency for NOG may be the cause for EA/TEF in the 17q deletion syndrome and suggests that the clinical spectrum of NOG-related symphalangism spectrum disorders may include EA/TEF.     

Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome

Proximal symphalangism is an autosomal-dominant disorder with ankylosis of the proximal interphalangeal joints, carpal and tarsal bone fusion, and conductive deafness. These symptoms are shared by another disorder of joint morphogenesis, multiple synostoses syndrome. Recently, it was reported that both disorders were caused by heterozygous mutations of the human noggin gene (NOG). To date, seven mutations of NOG have been identified from unrelated families affected with joint morphogenesis. To characterize the molecular lesions of proximal symphalangism, we performed analyses of NOG in three Japanese individuals with proximal symphalangism. We found three novel mutations: g.551G>A (C184Y) in a sporadic case of symphalangism, g.386T>A (L129X) in a familial case of symphalangism, and a g.58delC (frameshift) in a family with multiple synostosis syndrome. Characteristic genotype-phenotype correlations have not been recognized from the mutations in the NOG gene.     

A comprehensive review of reported heritable noggin-associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term: NOG-related-symphalangism spectrum disorder (NOG-SSD)

The NOG gene encodes noggin, a secreted polypeptide that is important for regulating multiple signaling pathways during human development, particularly in cartilage and bone. The hallmark of NOG-related syndromes is proximal symphalangism, defined by abnormal fusion of the proximal interphalangeal joints of the hands and feet. Many additional features secondary to NOG mutations are commonly but inconsistently observed, including a characteristic facies with a hemicylindrical nose, congenital conductive hearing loss due to stapes fixation, and hyperopia. The variable clinical presentations led to the designation of five different autosomal dominant syndromes, all subsequently found to have resulted from NOG mutations. These include (1) proximal symphalangism; (2) multiple synostoses syndrome 1; (3) stapes ankylosis with broad thumbs and toes; (4) tarsal-carpal coalition syndrome; and (5) brachydactyly type B2. Herein, we review the phenotypic features associated with mutations in the NOG gene, demonstrating the overlapping characteristics of these syndromes. Due to the variable phenotypic spectrum within families and among families with the same mutation, we propose a unifying term, NOG-related symphalangism spectrum disorder (NOG-SSD), to aid in the clinical recognition and evaluation of all affected individuals with these phenotypes. These NOG gene variants are available in a new locus-specific database (https://NOG.lovd.nl).     

Further delineation of the GDF6 related multiple synostoses syndrome

A mutation in GDF6 was recently found to underlie a multiple synostoses syndrome. In this report, we describe the second family with GDF6‐related multiple synostoses syndrome (SYNS4), caused by a novel c.1287C>A/p.Ser429Arg mutation in GDF6. In addition to synostoses of carpal and/or tarsal bones, at least 6 of 10 affected patients in this family have been diagnosed with mild to moderate hearing loss. In four of them otosclerosis was said to be present, one patient had hearing loss due to severe stapes fixation at the age of 6 years, providing evidence that hearing loss in the GDF6‐related multiple synostoses syndrome can be present in childhood. Two others had surgery for stapes fixation at adult age. We hypothesize that, identical to the recently published GDF6‐related multiple synostoses family, the p.Ser429Arg mutation also leads to a gain of function. The previously reported c.1330T>A/pTyr444Asn mutation was located in a predicted Noggin and receptor I interacting domain and the gain of function was partly due to resistance of the mutant GDF6 to the BMP‐inhibitor Noggin. The results in our family show that mutations predicting to affect the type II receptor interface can lead to a similar phenotype and that otosclerosis presenting in childhood can be part of the GDF6‐related multiple synostoses syndrome.     

Noggin heterozygous mice: an animal model for congenital conductive hearing loss in humans

Conductive hearing loss occurs when sound waves are not relayed efficiently to the inner ear. Mutations of the NOGGIN (NOG) gene in humans are associated with several autosomal dominant disorders such as proximal symphalangism and multiple synostoses. These syndromes are characterized by skeletal defects and synostoses, which include conductive hearing loss. Noggin is an antagonist of bone morphogenetic proteins (BMPs), and balanced levels of BMPs and Noggin are required for proper skeletal formation. Depending on the genetic background, some of the Nog(+/-) mice display mild hearing loss, that is, conductive in nature. Since Noggin is a single exon gene, this data strongly suggest that the autosomal dominant disorders associated with NOG mutations are due to haploinsufficiency of NOGGIN. The conductive hearing loss in Nog(+/-) mice is caused by an ectopic bone bridge located between the stapes and the posterior wall of the tympanum, which affects the normal mobility of the ossicle. Our analyses suggest that the ectopic bone formation is caused by a failure of the stapes and styloid process to separate completely during development. This failure of bone separation in the Nog(+/-) mice reveals another consequence of chondrocyte hyperplasia due to unopposed Bmp activities in these mutants such as Bmp4 and Bmp14 (Gdf5). More importantly, these results establish Nog(+/-) mice as the first animal model for the study of conductive rather than neurosensory hearing loss that has direct relevance to human genetic disorders.     

Congenital stapes ankylosis, broad thumbs, and hyperopia: report of a family and refinement of a syndrome

We report on a family with conductive hearing loss due to congenital stapes ankylosis, and with hyperopia, broad thumbs, and broad first toes. Neither of the studied relatives had symphalangism, possibly distinguishing this syndrome as an entity separate from the facio-audio-symphalangism and proximal symphalangism syndromes. An alternative possibility is that this family falls within the spectrum of the facioaudio-symphalangism and proximal symphalangism syndromes. Visualization of the ossicular chain, and ophthalmologic and radiologic studies are important in the evaluation of families with congenital conductive hearing loss. A characteristic physiognomy in our patients is present; this autosomal dominant syndrome was first described by Teunissen and Cremers [1990: Laryngoscope 100:380-384].     

A novel early truncation mutation in OTOG causes prelingual mild hearing loss without vestibular dysfunction

OTOG was identified as a nonsyndrmoic hearing loss gene in 2012 in two families with nonprogressive mild-to-moderate hearing loss. However, no further literature have this gene for nonsyndromic hearing loss. Furthermore, it is still unclear whether vestibular impairment is involved or not in patients with mutations in OTOG. This study presents a validated second report for homozygous causative mutations in OTOG of mild hearing loss. Whole exome sequencing (WES) was performed in a five-year-old male proband with mild hearing loss. The analysis of WES revealed a homozygous truncating mutation (c.330C > G; p.Tyr110*) in OTOG. The identified novel mutation, p.Tyr110*, leads to a null allele based on the fact that early truncated protein contains no functional domain of otogelin. While defects in otogelin previously reported to result in hearing loss and vestibular dysfunction, p.Tyr110* only caused nonsydromic and nonprogressive hearing loss without any vestibular impairment, indicating that vestibular phenotype would be variable. Given that mild hearing loss is not easy to be detected early, mutations of OTOG may be more prevalent than reported. Therefore, genetic evaluation for OTOG should be considered in children with mild hearing loss with/without vestibular dysfunction.     

一例Bainbridge-Ropers综合征患儿的基因变异分析

目的分析1例Bainbridge-Ropers综合征患儿及其父母ASXL3基因的变异类型,明确其可能的遗传学病因,为其临床诊断和遗传咨询提供依据。方法采集患儿和父母的外周血样,应用全外显子测序的方法对患儿基因进行检测,并采用Sanger测序的方法对变异位点进行验证。结果全外显子测序结果显示,患儿的ASXL3基因c.3106C>T杂合变异(p.Arg1036*),父母外周血ASXL3基因该位点未检测到c.3106C>T变异。该变异为无义变异,会产生截短蛋白。根据美国医学遗传学与基因组学学会变异分类标准与指南,c.3106C>T变异为致病性变异(PVS1+PS2+PP4)。结论ASXL3基因c.3106C>T杂合变异可能为患儿的致病原因,通过ASXL3基因变异分析,可以为其临床诊断和遗传咨询提供依据。     

一例 DIS3L2基因变异所致Perlman综合征患儿的临床表型及遗传学分析

目的:分析1例Perlman综合征患儿的临床表型及 DIS3L2基因变异,了解其可能的致病原因。 方法:抽取患儿及其父母外周血,对患儿进行全外显子测序分析,根据筛出致病基因变异对患儿及其父母进行Sanger测序验证。按照美国医学遗传学与基因组学学会(American College of Medi...     

Whole exome sequencing unravels disease‐causing genes in consanguineous families in Qatar

Whole exome sequencing (WES) has greatly facilitated the identification of causal mutations for diverse human genetic disorders. We applied WES as a molecular diagnostic tool to identify disease‐causing genes in consanguineous families in Qatar. Seventeen consanguineous families with diverse disorders were recruited. Initial mutation screening of known genes related to the clinical diagnoses did not reveal the causative mutations. Using WES approach, we identified the definitive disease‐causing mutations in four families: (i) a novel nonsense homozygous (c.1034C>G) in PHKG2 causing glycogen storage disease type 9C (GSD9C) in a male with initial diagnosis of GSD3; (ii) a novel homozygous 1‐bp deletion (c.915del) in NSUN2 in a male proband with Noonan‐like syndrome; (iii) a homozygous SNV (c.1598C>G) in exon 11 of IDUA causing Hurler syndrome in a female proband with unknown clinical diagnosis; (iv) a de novo known splicing mutation (c.1645+1G>A) in PHEX in a female proband with initial diagnosis of autosomal recessive hypophosphatemic rickets. Applying WES as a diagnostic tool led to the unambiguous identification of disease‐causing mutations in phenotypically complex disorders or correction of the initial clinical diagnosis in ?25% of our cases.     

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.     

Molecular and clinical delineation of the 17q22 microdeletion phenotype

Deletions involving 17q21–q24 have been identified previously to result in two clinically recognizable contiguous gene deletion syndromes: 17q21.31 and 17q23.1–q23.2 microdeletion syndromes. Although deletions involving 17q22 have been reported in the literature, only four of the eight patients reported were identified by array-comparative genomic hybridization (array-CGH) or flourescent in situ hybridization. Here, we describe five new patients with 1.8–2.5-Mb microdeletions involving 17q22 identified by array-CGH. We also present one patient with a large karyotypically visible deletion involving 17q22, fine-mapped to ∼8.2 Mb using array-CGH. We show that the commonly deleted region in our patients spans 0.24 Mb and two genes; NOG and C17ORF67. The function of C17ORF67 is not known, whereas Noggin, the product of NOG, is essential for correct joint development. In common with the 17q22 patients reported previously, the disease phenotype of our patients includes intellectual disability, attention deficit hyperactivity disorder, conductive hearing loss, visual impairment, low set ears, facial dysmorphology and limb anomalies. All patients displayed NOG-related bone and joint features, including symphalangism and facial dysmorphology. We conclude that these common clinical features indicate a novel clinically recognizable, 17q22 contiguous microdeletion syndrome.     

FGF9 mutation causes craniosynostosis along with multiple synostoses

Craniosynostosis is commonly caused by mutations in fibroblast growth factor receptors (FGFRs), highlighting the essential role of FGF‐mediated signaling in skeletal development. We set out to identify the molecular defect in a family referred for craniosynostosis and in whom no mutation was previously detected. Using next‐generation sequencing, we identified a novel missense mutation in FGF9. Modeling based upon the crystal structure and functional studies confirmed its pathogenicity showing that it impaired homodimerization and FGFR3 binding. Only one FGF9 mutation has been previously reported in a multigeneration family with multiple synostoses (SYNS3) but no signs of craniosynostosis. In contrast, our family has a greater phenotypic resemblance to that observed in the Fgf9 spontaneous mouse mutant, elbow‐knee‐synostosis, Eks, with both multiple synostoses and craniosynostosis. We have demonstrated for the first time that mutations in FGF9 cause craniosynostosis in humans and confirm that FGF9 mutations cause multiple synostoses.     

The third case of Marbach-Rustad progeroid syndrome caused by a de novo LEMD2 variant

Marbach-Rustad progeroid syndrome is an extremely rare disease caused by a heterozygous variant in the LEMD2 gene. To date, only two patients and one LEMD2 pathogenic variant have been reported in Marbach-Rustad progeroid syndrome. Here we describe the third case of Marbach-Rustad progeroid syndrome worldwide, which is also the first case in China. The proband was affected with premature birth, failed to thrive, facial abnormalities, feeding difficulties, skull defects and delayed motor milestones, but had a normal intelligence and speech. Whole exome sequencing (WES) initially did not find a phenotype-causing variant when the proband was 1 year of age. The reanalysis of WES data 4 years later revealed the proband harbored a de novo heterozygous c.1436C>T(p.Ser479Phe) variant in the LEMD2 gene, which is known responsible for Marbach-Rustad progeroid syndrome. Sanger sequencing confirmed the presence of this variant in the proband and absence in his parents and two elder sisters. Our study provides accurate clinical diagnosis for the proband and adds a new patient with Marbach-Rustad progeroid syndrome. Our study suggests the LEMD2 c.1436C>T(p.Ser479Phe) variant as a hotspot. Our work also indicates reanalysis of WES data of negative cases might identify pathogenic variant and improve diagnostic efficiency.     

一例视网膜色素变性患者 C2ORF71基因的变异分析

目的:分析1例视网膜色素变性(retinitis pigmentosa, RP)患者的基因变异,明确其可能的遗传学病因。方法:应用全外显子测序技术对先证者进行致病基因筛查,结合临床表型确定可疑变异,应用Sanger测序法验证检出的变异,分析双亲携带变异位点的情况。采用多种软件对所检出的变异进行致病性分析。结果:全外显子...     

Herrmann multiple synostosis syndrome with neurological complications caused by spinal canal stenosis

A young man was found to have multiple synostosis syndrome type I after presenting with a neck injury causing a cervical spinal cord contusion. Neurological symptoms and signs suggested spinal cord compression. Magnetic resonance (MR) and computerized tomography (CT) imaging of the spine showed spinal canal stenosis with cord compression at C3-C6, a deformed spinal canal flattened in the anteroposterior dimension, vertebral fusions and deformed lateral processes of the vertebrae. He had a long broad nose with hypoplasia of the alae nasi, conductive hearing loss requiring hearing aids, muscular build, stiff spine, prominent acromia, pectus excavatum, ischial prominences, short fifth fingers, fusion at the proximal interphalangeal joints of the fifth fingers with indistinct overlying creases, and toe syndactyly. Spinal cord stenosis is a serious complication of multiple synostosis syndrome, that should be kept in mind in considering the risk of neck or back injury associated with certain sports or other activities. In both the multiple synostosis syndrome and the less severe proximal symphalangism deafness syndrome, mutations have been detected in the human homologue of the noggin gene on chromosome 17q21-q22.     

一例早发癫痫性脑病42型患儿的临床表型及基因变异分析

目的探讨一例早发癫痫性脑病42型患儿的基因型与表型特征。方法详细询问患儿的病史,结合其临床表型、影像学及遗传学特征进行临床诊断,并对其父母进行Sanger测序验证,明确致病变异的来源。结果患儿无意识头向一侧轻度歪斜,眼球向同侧斜视,脑电图异常放电。磁共振成像显示左额后皮层可疑异常信号,伴右侧上颌窦及筛窦炎症。全外显子组测序提示患儿携带CACNA1A基因c.5789G>A杂合变异,Sanger测序提示父母双方并未携带相同的变异,提示其为新发变异。结论先证者CACNA1A基因c.5789G>A杂合变异可能是导致其早发癫痫性脑病42型的原因。     

Mosaic KCNJ2 mutation in Andersen–Tawil syndrome: targeted deep sequencing is useful for the detection of mosaicism

Andersen–Tawil syndrome (ATS) is an inherited disease characterized by ventricular arrhythmias, periodic paralysis, and dysmorphic features. It results from a heterozygous mutation of KCNJ2, but little is known about mosaicism in ATS. We performed genetic analysis of KCNJ2 in 32 ATS probands and their family members and identified KCNJ2 mutations in 25 probands, 20 families who underwent extensive genetic testing. These tests revealed that seven probands carried de novo mutations while 13 carried inherited mutations from their parents. We then specifically assessed a single proband and the respective family. The proband was a 9 year old girl who fulfilled the ATS triad and carried an insertion mutation (p.75_76insThr). We determined that the proband's mother carried a somatic mosaicism and that the proband's younger brother also carried the ATS phenotype with the same insertion mutation. The mother, who exhibited mosaicism, was asymptomatic, although she exhibited Q(T)U prolongation. Mutant allele frequency was 11% as per TA cloning and 17.3% as per targeted deep sequencing. Our observations suggest that targeted deep sequencing is useful for the detection of mosaicism and that the detection of mosaic mutations in parents of apparently sporadic ATS patients can help in the process of genetic counseling.     

Further delineation of CDC45-related Meier-Gorlin syndrome with craniosynostosis and review of literature

Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by the triad of short stature, microtia and absent or small patellae. We report on a patient with MGS secondary to biallelic mutations in CDC45 detected on whole exome sequencing (WES). Patients with MGS caused by mutations in CDC45 display a distinct phenotype characterized by craniosynostosis and anorectal malformation. Our patient had craniosynostosis, anorectal malformation and short stature, but did not have the microtia or patella hypoplasia. Our report also highlights the value of WES in aiding diagnosis of patients with rare genetic diseases. In conclusion, our case report and review of the literature illustrates the unique features of CDC45-related MGS as well as the benefits of WES in reducing the diagnostic odyssey for patients with rare genetic disorders.