Expanding the phenotypic spectrum of IFT81: Associated ciliopathy syndrome

Short‐rib polydactyly syndromes are a heterogeneous group of disorders characterized by narrow thorax with short ribs, polydactyly and often other visceral and skeletal malformations. To date there have only been six reported patients with homozygous and compound heterozygous variants in IFT81, causing a short‐rib thoracic dysplasia, with, or without, polydactyly (SRTD19: OMIM 617895). IFT81 is a protein integral to the core of the intraflagellar transport complex B (IFT‐B), which is involved in anterograde transport in the cilium. We describe the case of a male infant with compound heterozygous variants in IFT81, who presented with short long bones, a narrow thorax, polydactyly, and multiple malformations. Three novel clinical features are reported including complete situs inversus, micropenis, and rectal atresia, which have not previously been associated with variants in IFT81. We reviewed the literature and identified the most consistent clinical features associated with this rare ciliopathy syndrome. We postulate that dolichocephaly and sagittal craniosynostosis may be associated with this condition, and provide a clue to considering IFT81 as the causative gene when deciphering complex ciliopathies.     

TBC1D7 Mutations are Associated with Intellectual Disability,Macrocrania, Patellar Dislocation,and Celiac Disease

TBC1D7 forms a complex with TSC1 and TSC2 that inhibits mTORC1 signaling and limits cell growth. Mutations in TBC1D7 were reported in a family with intellectual disability (ID) and macrocrania. Using exome sequencing, we identified two sisters homozygote for the novel c.17_20delAGAG, p.R7TfsX21 TBC1D7 truncating mutation. In addition to the already described macrocephaly and mild ID, they share osteoarticular defects, patella dislocation, behavioral abnormalities, psychosis, learning difficulties, celiac disease, prognathism, myopia, and astigmatism. Consistent with a loss‐of‐function of TBC1D7, the patient's cell lines show an increase in the phosphorylation of 4EBP1, a direct downstream target of mTORC1 and a delay in the initiation of the autophagy process. This second family allows enlarging the phenotypic spectrum associated with TBC1D7 mutations and defining a TBC1D7 syndrome. Our work reinforces the involvement of TBC1D7 in the regulation of mTORC1 pathways and suggests an altered control of autophagy as possible cause of this disease.     

Expanding the MYBPC1 phenotypic spectrum: a novel homozygous mutation causes arthrogryposis multiplex congenita

Arthrogryposis multiplex congenita (AMC) is characterized by heterogeneous nonprogressive multiple joint contractures appearing at birth. We present a consanguineous Israeli‐Druze family with several members presenting with AMC. A variable intra‐familial phenotype and pected autosomal recessive inheritance prompted molecular diagnosis by whole‐exome sequencing. Variant analysis focused on rare homozygous changes, revealed a missense variant in MYBPC1, NM_002465:c.556G>A (p.E286K), affecting the last nucleotide of Exon 8. This novel variant was not observed in the common variant databases and co‐segregated as expected within the extended family. MYBPC1 encodes a slow skeletal muscle isoform, essential for muscle contraction. Heterozygous mutations in this gene are associated with distal arthrogryposis types 1b and 2, whereas a homozygous nonsense mutation is implicated in one family with lethal congenital contractural syndrome 4. We present a novel milder MYBPC1 homozygous phenotype.     

Novel Compound Heterozygous Mutations in TBC1D24 Cause Familial Malignant Migrating Partial Seizures of Infancy

Early‐onset epileptic encephalopathies (EOEEs) are a group of rare devastating epileptic syndromes of infancy characterized by severe drug‐resistant seizures and electroencephalographic abnormalities. The current study aims to determine the genetic etiology of a familial form of EOEE fulfilling the diagnosis criteria for malignant migrating partial seizures of infancy (MMPSI). We identified two inherited novel mutations in TBC1D24 in two affected siblings. Mutations severely impaired TBC1D24 expression and function, which is critical for maturation of neuronal circuits. The screening of TBC1D24 in an additional set of eight MMPSI patients was negative. TBC1D24 loss of function has been associated to idiopathic infantile myoclonic epilepsy, as well as to drug‐resistant early‐onset epilepsy with intellectual disability. Here, we describe a familial form of MMPSI due to mutation in TBC1D24, revealing a devastating epileptic phenotype associated with TBC1D24 dysfunction.     

Ciliary Genes TBC1D32/C6orf170 and SCLT1 are Mutated in Patients with OFD Type IX

Clinical syndromes caused by defects in the primary cilium are heterogeneous but there are recurrent phenotypic manifestations that define them as a collective group known as ciliopathies. Dozens of genes have been linked to various ciliopathies but large patient cohorts have clearly revealed the existence of additional genetic heterogeneity, which is yet to be fully appreciated. In our search for novel ciliopathy‐linked genes through the study of unmapped ciliopathy phenotypes, we have identified two simplex cases with a severe ciliopathy phenotype consistent with oro‐facio‐digital syndrome type IX featuring midline cleft, microcephaly, and colobomatous microphathalmia/anophthalmia. In addition, there was variable presence of polydactyly, absent pituitary, and congenital heart disease. The autozygome of each index harbored a single novel truncating variant as revealed by exome sequencing, and the affected genes (SCLT1 and TBC1D32/C6orf170) have established roles in centrosomal biology and ciliogenesis. Our findings suggest a previously unrecognized role of SCLT1 and TBC1D32 in the pathogenesis of ciliopathy in humans.     

Expanding the phenotypic spectrum associated with OPHN1 variants

Genomic sequencing has allowed for the characterization of new gene-to-disease relationships, as well as the identification of variants in established disease genes in patients who do not fit the classically-described phenotype. This is especially true in rare syndromes where the clinical spectrum is not fully known. After a lengthy and costly diagnostic odyssey, patients with atypical presentations may be left with many questions even after a genetic diagnosis is identified. We present a 22-year old male with hypotonia, developmental delay, seizure disorder, and dysmorphic facial features who enrolled in our rare disease research center at 18 years of age, where exome sequencing revealed a novel, likely pathogenic variant in the OPHN1 gene. Through efforts by the study team and collaborations with the larger genetics community, contacts with other families with OPHN1 variants were eventually made, and outreach by these families expanded the patient network. This partnership between families and researchers facilitated the gathering of phenotypic information, allowing for comparison of clinical presentations among three new patients and those previously reported in the literature. These comparisons found previously unreported commonalities between the newly identified patients, such as the presence of otitis media and the lack of genitourinary abnormalities (i.e. hypoplastic scrotum, microphallus, cryptorchidism), which had been noted to be classic features of patients with OPHN1 variants. As genomic sequencing becomes more common, connecting patients with novel variants in the same gene will facilitate phenotypic analysis and continue to refine the clinical spectrum associated with that gene.     

Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype

Gene discovery using massively parallel sequencing has focused on phenotypes diagnosed postnatally such as well‐characterized syndromes or intellectual disability, but is rarely reported for fetal disorders. We used family‐based whole‐exome sequencing in order to identify causal variants for a recurrent pattern of an undescribed lethal fetal congenital anomaly syndrome. The clinical signs included intrauterine growth restriction (IUGR), severe microcephaly, renal cystic dysplasia/agenesis and complex brain and genitourinary malformations. The phenotype was compatible with a ciliopathy, but not diagnostic of any known condition. We hypothesized biallelic disruption of a gene leading to a defect related to the primary cilium. We identified novel autosomal recessive truncating mutations in KIF14 that segregated with the phenotype. Mice with autosomal recessive mutations in the same gene have recently been shown to have a strikingly similar phenotype. Genotype–phenotype correlations indicate that the function of KIF14 in cell division and cytokinesis can be linked to a role in primary cilia, supported by previous cellular and model organism studies of proteins that interact with KIF14. We describe the first human phenotype, a novel lethal ciliary disorder, associated with biallelic inactivating mutations in KIF14. KIF14 may also be considered a candidate gene for allelic viable ciliary and/or microcephaly phenotypes.     

Expanding the phenotypic spectrum of MBOAT7‐related intellectual disability

MBOAT7 gene pathogenic variants are a newly discovered and rare cause for intellectual disability, autism spectrum disorder (ASD), seizures, truncal hypotonia, appendicular hypertonia, and below average head sizes (ranging from ?1 to ?3 standard deviations). There have been only 16 individuals previously reported who have MBOAT7‐related intellectual disability, all of whom were younger than 10 years old and from consanguineous relationships. Thus, there is a lack of phenotypic information for adolescent and adult individuals with this disorder. Medical genetics and psychiatric evaluations in a 14‐year‐old female patient with a history of global developmental delay, intellectual disability, overgrowth with macrocephaly, metrorrhagia, seizures, basal ganglia hyperintensities, nystagmus, strabismus with amblyopia, ASD, anxiety, attention deficit hyperactivity disorder (ADHD), aggressive outbursts, and hyperphagia included a karyotype, methylation polymerase chain reaction for Prader‐Willi/Angelman syndrome, chromosome microarray, and whole exome sequencing (WES), ADOS2, and ADI‐R. WES identified a homozygous, likely pathogenic variant in the MBOAT7 gene (c.855‐2A>G). This is the oldest known patient with MBOAT7‐related intellectual disability, whose unique features compared with previously described individuals include overgrowth with macrocephaly, metrorrhagia, ophthalmological abnormalities, basal ganglia hyperintensities, unspecified anxiety disorder, and ADHD; combined type; and hyperphagia with the absence of appendicular hypertonia and cortical atrophy. More individuals need to be identified in order to delineate the full clinical spectrum of this disorder.     

PRUNE1‐related disorder: Expanding the clinical spectrum

Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA) (OMIM #617481) is an autosomal recessive disease characterized by progressive microcephaly, plagiocephaly, hypotonia, spastic quadriparesis, global developmental delay, intellectual disability, optic features and abnormal brain magnetic resonance imaging (MRI). NMIHBA was recently reported to be caused by PRUNE1 mutations. Eight mutations have been reported in 13 unrelated families. Here, we report 3 PRUNE1 mutations in 1 Caucasian and 3 Japanese families. One recurrent missense mutation (p.Asp106Asn) was previously reported in Turkish and Italian families, while the other 2 mutations (p.Leu18Serfs*8 and p.Cys180*) are novel. We also show that mutant PRUNE1 mRNA can be subject to nonsense‐mediated mRNA decay. The patients presented in this study showed atypical NMIHBA phenotypes with no progressive microcephaly. Furthermore, one Caucasian case had significant macrocephaly; therefore, patients with PRUNE1 mutations can exhibit a broad and heterogeneous spectrum of phenotypes.     

Expanding the phenotypic spectrum associated with DPF2: A new case report

Coffin–Siris syndrome (CSS) is a clinically and genetically heterogeneous developmental disorder, linked to disruption of the BAF chromatin‐remodeling complex. Recently, de novo missense and truncating variants have been reported in DPF2 in patients sharing some of the common features of CSS. Here we report a further individual harboring a novel de novo missense DPF2 variant, c.1066T>G, p.Cys356Gly. Structural modeling indicated that the predicted amino acid substitution affects a core residue required for zinc ion coordination and would likely alter the PHD2 domain structure of DPF2. The clinical presentation of Pierre Robin sequence and diaphragmatic hernia did not immediately suggest CSS, with the more common CSS features of hypoplastic toenails and characteristic facial features very subtle. This individual further broadens the phenotypic features of DPF2‐related CSS, as well as CSS more generally.     

Expanding the phenotypic spectrum of ARCN1-related syndrome

PurposeThis study aimed to describe the phenotypic and molecular characteristics of ARCN1-related syndrome.MethodsPatients with ARCN1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient.ResultsIn total, we identified 14 cases of ARCN1-related syndrome, (9 pediatrics, and 5 fetal cases from 3 families). The clinical features these newly identified cases were compared to 6 previously reported cases for a total of 20 cases. Intrauterine growth restriction, micrognathia, and short stature were present in all patients. Other common features included prematurity (11/15, 73.3%), developmental delay (10/14, 71.4%), genitourinary malformations in males (6/8, 75%), and microcephaly (12/15, 80%). Novel features of ARCN1-related syndrome included transient liver dysfunction and specific glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, cataracts, and lethal skeletal manifestations. Developmental delay was seen in 73% of patients, but only 3 patients had intellectual disability, which is less common than previously reported.ConclusionARCN1-related syndrome presents with a wide clinical spectrum ranging from a severe embryonic lethal syndrome to a mild syndrome with intrauterine growth restriction, micrognathia, and short stature without intellectual disability. Patients with ARCN1-related syndrome should be monitored for liver dysfunction during illness, cataracts, and hepatoblastoma. Additional research to further define the phenotypic spectrum and possible genotype–phenotype correlations are required.     

Expanding the molecular basis and phenotypic spectrum of X-linked Joubert syndrome associated with OFD1 mutations

Using a combination of linkage mapping and massively parallel sequencing of the X-chromosome exome, we identified an 18-bp deletion in exon 8 of the oral-facial-digital syndrome type 1 (OFD1) gene in a family with X-linked Joubert syndrome (JBTS10). The deletion results in an in-frame deletion of six amino acids. New features not noted in the two previously reported cases of X-linked Joubert syndrome include the presence of polycystic kidney disease, polymicrogyria and hydrocephalus. Our study further underlines the power of genetic mapping combined with massively parallel sequencing as a powerful tool for novel disease gene and mutation discovery.