Novel Mutations Including Deletions of the Entire OFD1 Gene in 30 Families with Type 1 Orofaciodigital Syndrome: A Study of the Extensive Clinical Variability

OFD1, now recognized as a ciliopathy, is characterized by malformations of the face, oral cavity and digits, and is transmitted as an X‐linked condition with lethality in males. Mutations in OFD1 also cause X‐linked Joubert syndrome (JBTS10) and Simpson–Golabi–Behmel syndrome type 2 (SGBS2). We have studied 55 sporadic and six familial cases of suspected OFD1. Comprehensive mutation analysis in OFD1 revealed mutations in 37 female patients from 30 families; 22 mutations have not been previously described including two heterozygous deletions spanning OFD1 and neighbouring genes. Analysis of clinical findings in patients with mutations revealed that oral features are the most reliable diagnostic criteria. A first, detailed evaluation of brain MRIs from seven patients with cognitive defects illustrated extensive variability with the complete brain phenotype consisting of complete agenesis of the corpus callosum, large single or multiple interhemispheric cysts, striking cortical infolding of gyri, ventriculomegaly, mild molar tooth malformation and moderate to severe cerebellar vermis hypoplasia. Although the OFD1 gene apparently escapes X‐inactivation, skewed inactivation was observed in seven of 14 patients. The direction of skewing did not correlate with disease severity, reinforcing the hypothesis that additional factors contribute to the extensive intrafamilial variability.     

A novel pathogenic variant in OFD1 results in X‐linked Joubert syndrome with orofaciodigital features and pituitary aplasia

Orofaciodigital syndrome type I and X‐linked recessive Joubert syndrome are known ciliopathic disorders that are caused by pathogenic variants in OFD1 gene. Endocrine system involvement with these conditions is not well described. We present the first report of a newborn male with a novel hemizygous variant in OFD1 gene c.515T>C, (p.Leu172Pro) resulting in X‐linked Joubert syndrome and orofaciodigital features with complete pituitary gland aplasia and subsequent severe hypoplasia of peripheral endocrine glands. This clinical report expands the phenotypic spectrum of endocrine system involvement in OFD1‐related disorders and suggests that OFD1 gene may be related to pituitary gland development.     

Oral‐facial‐digital syndrome type 1 in males: Congenital heart defects are included in its phenotypic spectrum

Oral‐facial‐digital syndrome type 1 (OFD1; OMIM# 311200) is an X‐linked dominant ciliopathy caused by mutations in the OFD1 gene. This condition is characterized by facial anomalies and abnormalities of oral tissues, digits, brain, and kidneys. Almost all affected patients are female, as OFD1 is presumed to be lethal in males, mostly in the first or second trimester of pregnancy. Live born males with OFD1 are a rare occurrence, with only five reported patients to date. In four patients the presence of a congenital heart defect (CHD) was observed. Here, we report an affected male fetus with a hemizygous de novo mutation in OFD1 (c.2101C>T; p.(Gln701*)). Ultrasound examination demonstrated severe hydrocephalus, a hypoplastic cerebellum and a hypoplastic left ventricle of the heart. The pregnancy was terminated at 16 weeks of gestation because of poor prognosis. Post‐mortem examination of the fetus confirmed severe hypoplasia of the left ventricle of the heart. We emphasize that CHDs should be included in the phenotypic spectrum of OFD1 in males. This justifies molecular analysis of OFD1 when CHD is encountered prenatally in combination with one or more phenotypic features previously described in the OFD1 gene alteration spectrum. The underlying pathogenesis of CHD in OFD1 (and other ciliopathies) probably involves dysfunction of the primary cilia regarding coordination of left‐right signalling during early heart development. Whether these CHDs wholly or partly result from defective left right signalling, in which different types of cilia are known to play a critical role, remains a topic of research.     

Clinical, molecular, and genotype-phenotype correlation studies from 25 cases of oral-facial-digital syndrome type 1: a French and Belgian collaborative study

Oral–facial–digital syndrome type 1 (OFD1) is characterised by an X linked dominant mode of inheritance with lethality in males. Clinical features include facial dysmorphism with oral, tooth, and distal abnormalities, polycystic kidney disease, and central nervous system malformations. Large interfamilial and intrafamilial clinical variability has been widely reported, and 18 distinct mutations have been previously reported within OFD1. A French and Belgian collaborative study collected 25 cases from 16 families. OFD1 was analysed using direct sequencing and phenotype–genotype correlation was performed using χ² test. X inactivation studies were performed on blood lymphocytes. In 11 families, 11 novel mutations, including nine frameshift, one nonsense, and one missense mutation were identified, which spanned nine different exons. A combination of our results with previously reported cases showed that the majority of mutations (65.5%) was located in exons 3, 8, 9, 13, and 16. There was phenotype–genotype correlation between (a) polycystic kidney disease and splice mutations; (b) mental retardation and mutations located in exons 3, 8, 9, 13, and 16; and (c) tooth abnormalities and mutations located in coiled coil domains. Comparing the phenotype of the families with a pathogenic mutation to families with absence of OFD1 mutation, polycystic kidneys and short stature were significantly more frequent in the group with no OFD1 mutation, whereas lingual hamartomas were significantly more frequent in the group with OFD1 mutation. Finally, an X inactivation study showed non‐random X inactivation in a third of the samples. Differential X inactivation between mothers and daughters in two families with high intrafamilial variability was of particular interest. Slight phenotype–genotype correlations were established, and X inactivation study showed that skewed X inactivation could be partially involved in the pathogenesis of intrafamilial clinical variability.     

Indian child with novel variant in OFD1 gene

Orofaciodigital syndrome (OFD) can have variable phenotype and presents with oral anomalies, facial dysmorphism, and digital malformations like syndactyly, and polydactyly. Other presentations also include renal and cardiac defects, and central nervous system anomalies like hydrocephalus and cerebellar abnormalities. OFD1 is a X‐linked dominant form of the syndrome presenting in females with mutations in CXorf5 or OFD1 gene. We describe a young child with sparse hairs, milia over face and absence of corpus callosum. Next generation sequencing showed frameshift pathogenic variant in the exon 13 of the OFD1 gene, consistent with diagnosis of OFD1.     

Renal insufficiency,a frequent complication with age in oral‐facial‐digital syndrome type I

Saal S, Faivre L, Aral B, Gigot N, Toutain A, Van Maldergem L, Destree A, Maystadt I, Cosyns J‐P, Jouk P‐S, Loeys B, Chauveau D, Bieth E, Layet V, Mathieu M, Lespinasse J, Teebi A, Franco B, Gautier E, Binquet C, Masurel‐Paulet A, Mousson C, Gouyon J‐B, Huet F, Thauvin‐Robinet C. Renal insufficiency, a frequent complication with age in oral‐facial‐digital syndrome type I. The oral‐facial‐digital syndrome type I (OFD I) is characterized by multiple congenital malformations of the face, oral cavity and digits. A polycystic kidney disease (PKD) is found in about one‐third of patients but long‐term outcome and complications are not well described in the international literature. Renal findings have been retrospectively collected in a cohort of 34 females all carrying a pathogenic mutation in the OFD1 gene with ages ranging from 1 to 65 years. Twelve patients presented with PKD – 11/16 (69%) if only adults were considered –with a median age at diagnosis of 29 years [IQR (interquartile range) = (23.5–38)]. Among them, 10 also presented with renal impairment and 6 were grafted (median age = 38 years [IQR = (25–48)]. One grafted patient under immunosuppressive treatment died from a tumor originated from a native kidney. The probability to develop renal failure was estimated to be more than 50% after the age of 36 years. Besides, neither genotype‐phenotype correlation nor clinical predictive association with renal failure could be evidenced. These data reveal an unsuspected high incidence rate of the renal impairment outcome in OFD I syndrome. A systematic ultrasound (US) and renal function follow‐up is therefore highly recommended for all OFD I patients.     

Cenani–Lenz syndrome and other related syndactyly disorders due to variants in LRP4, GREM1/FMN1, and APC: Insight into the pathogenesis and the relationship to polyposis through the WNT and BMP antagonistic pathways

Cenani–Lenz (C–L) syndrome is characterized by oligosyndactyly, metacarpal synostosis, phalangeal disorganization, and other variable facial and systemic features. Most cases are caused by homozygous and compound heterozygous missense and splice mutations of the LRP4 gene. Currently, the syndrome carries one OMIM number (212780). However, C–L syndrome‐like phenotypes as well as other syndactyly disorders with or without metacarpal synostosis/phalangeal disorganization are also known to be associated with specific LRP4 mutations, adenomatous polyposis coli (APC) truncating mutations, genomic rearrangements of the GREM1‐FMN1 locus, as well as FMN1 mutations. Surprisingly, patients with C–L syndrome‐like phenotype caused by APC truncating mutations have no polyposis despite the increased levels of β catenin. The LRP4 and APC proteins act on the WNT (wingless‐type integration site family) canonical pathway, whereas the GREM‐1 and FMN1 proteins act on the bone morphogenetic protein (BMP) pathway. In this review, we discuss the different mutations associated with C–L syndrome, classify its clinical features, review familial adenomatous polyposis caused by truncating APC mutations and compare these mutations to the splicing APC mutation associated with syndactyly, and finally, explore the pathophysiology through a review of the cross talks between the WNT canonical and the BMP antagonistic pathways.     

A novel truncating variant in ring finger protein 113A (RNF113A) confirms the association of this gene with X‐linked trichothiodystrophy

We describe an 11‐year old boy with severe global developmental delays, failure to thrive and growth retardation, refractory seizures with recurrent status epilepticus, hypogammaglobulinemia, hypergonadotropic hypogonadism, and duodenal strictures. He had facial and skin findings compatible with trichothiodystrophy, including sparse and brittle hair, thin eyebrows, and dry skin. Exome sequencing showed a hemizygous, truncating variant in RNF113A, c.903_910delGCAGACCA, predicting p.(Gln302fs*12), that was inherited from his mother. Although his clinical features overlap closely with features described in the two previously reported male first cousins with RNF113A loss of function mutations, the duodenal strictures seen in this patient have not been reported. Interestingly, the patient's mother had short stature and 100% skewed X‐inactivation as seen in other obligate female carriers. A second male with developmental delays, microcephaly, seizures, ambiguous genitalia, and facial anomalies that included sparse and brittle hair, thin eyebrows and dry skin was recently reported to have c.897_898delTG, predicting p.(Cys299*) in RNF113A and we provide additional clinical details for this patient. This report further supports deleterious variants in RNF113A as a cause of a novel trichothiodystrophy syndrome.     

SOFT syndrome in a patient from Chile

SOFT syndrome (MIM614813) is an extremely rare primordial dwarfism caused by biallelic mutations in the POC1A gene. It is characterized by prenatal short stature, onychodysplasia, facial dysmorphism, hypotrichosis, and variable skeletal abnormalities including hypoplastic pelvis and sacrum, small hands, and cone‐shaped epiphyses, as well as delayed bone age. To the best of our knowledge, only eight POC1A mutations have been reported in humans to date. We report a 7‐year‐old Chilean girl with SOFT syndrome arising from a novel POC1A mutation c. 649C>T, p.Arg217Trp. Although her clinical features were largely compatible with SOFT syndrome, hand X‐ray examinations at 3.5 and 6 years unexpectedly showed normal bone age. Automated bone age determination was performed using image analysis software, BoneXpert. This case highlights the importance of the accumulation of patients with POC1A mutations to further elucidate the detailed clinical features of SOFT syndrome.     

Clinical spectrum of Kabuki‐like syndrome caused by HNRNPK haploinsufficiency

Kabuki syndrome is a genetically heterogeneous disorder characterized by postnatal growth retardation, skeletal abnormalities, intellectual disability, facial dysmorphisms and a variable range of organ malformations. In ~30% of affected individuals, the underlying genetic defect remains unknown. A small number of inactivating heterozygous HNRNPK mutations has recently been reported to be associated with a condition partially overlapping or suggestive of Kabuki syndrome. Here, we report on an 11‐year‐old girl with a complex phenotype in whom the diagnosis of KS was suggested but molecular testing for the known causative disease genes was negative. Whole‐exome sequencing identified a previously undescribed de novo truncating mutation in HNRNPK as the molecular defect underlying the trait. Analysis of available records of patients with HNRNPK haploinsufficiency was performed to delineate the associated clinical phenotype and outline their distinguishing features in comparison with the KS clinical spectrum. The clinical profile associated with inactivating HNRNPK mutations supports the idea that the associated disorder should be considered as a distinct nosologic entity clinically related to KS, and that the condition should be considered in differential diagnosis with KS, in particular in subjects exhibiting brain malformation (nodular heterotopia), craniosynostosis, and polydactyly.     

Expanding the phenotype of males with OFD1 pathogenic variants-a case report and literature review

Pathogenic variants in the OFD1 gene have been classically associated with the Orofaciodigital syndrome type 1 in females, a condition previously considered to be X-linked dominant with male embryonic lethality. However, an increasing number of males with pathogenic OFD1 variants who survived beyond the neonatal period have now been reported in the literature. Although each new report has added to the ever-broadening spectrum of clinical findings seen in males, many questions about genotype-phenotype correlations and disease mechanism remain. Herein, we describe a 9-year-old male child with a novel hemizygous pathogenic OFD1 variant identified by exome sequencing and a unique combination of findings, not previously reported, including presence of both a hypothalamic hamartoma and the molar tooth sign. His clinical features overlap multiple ciliopathy phenotypes, blurring the boundaries of distinct ciliopathy gene-disease relationships. This case provides further evidence for the consideration of a broad OFD1-relateddisorder spectrum in affected males rather than multiple distinct phenotypes. Additionally, a review of previously published cases of the disorder in males support the inclusion of the OFD1 gene in the differential diagnosis and work up for all individuals who present with primary ciliopathy-type features, regardless of their gender. We also highlight current information about OFD1 variant types and pathogenesis and explore how these could mechanistically drive some of the observed phenotypic differences.     

De novo mutations of the gene encoding the histone acetyltransferase KAT6B in two patients with Say‐Barber/Biesecker/Young‐Simpson syndrome

The Say‐Barber/Biesecker/Young‐Simpson (SBBYS) type of the blepharophimosis–mental retardation syndrome group (Ohdo‐like syndromes) is a multiple congenital malformation syndrome characterized by vertical narrowing and shortening of the palpebral fissures, ptosis, intellectual disability, hypothyroidism, hearing impairment, and dental anomalies. Mutations of the gene encoding the histone‐acetyltransferase KAT6B have been recently identified in individuals affected by SBBYS syndrome. SBBYS syndrome‐causing KAT6B mutations cluster in a ～1,700 basepair region in the 3′ part of the large exon 18, while mutations located in the 5′ region of the same exon have recently been identified to cause the genitopatellar syndrome (GPS), a clinically distinct although partially overlapping malformation‐intellectual disability syndrome. Here, we present two children with clinical features of SBBYS syndrome and de novo truncating KAT6B mutations, including a boy who was diagnosed at the age of 4 months. Our results confirm the implication of KAT6B mutations in typical SBBYS syndrome and emphasize the importance of genotype–phenotype correlations at the KAT6B locus where mutations truncating the KAT6B protein at the amino‐acid positions ～1,350–1,920 cause SBBYS syndrome. © 2013 Wiley Periodicals, Inc.     

Preserved speech variants of the Rett syndrome: Molecular and clinical analysis

Mutations in the MECP2 gene cause the severe neurodevelopmental disorder called Rett syndrome. Preliminary evidence suggests that MECP2 may be involved in a broader phenotype than classical Rett syndrome including preserved speech variants (PSV). Here we report clinical and mutation analysis of 18 PSV patients. Ten of them had a MECP2 mutation (55%). The clinical features of these girls have been characterized and two subgroups defined. All of them had slow recovery of verbal and praxic abilities, evident autistic behavior, and normal head circumference. Six were overweight, often obese, had kyphosis, coarse face, and mental age of two‐to‐three years, and were able to speak in sentences; four had normal weight, mental age not beyond one‐to‐two years, and spoke in single words and two‐word phrases. The course of the disorder was in stages as in classic Rett syndrome. Hand‐washing was present in the first years of life but often subsequently disappeared. Significantly, all mutations found in PSV are either missense or late truncating mutations. In particular, we did not find the four early truncating hot spots: R168X, R255X, R270X, R294X. These results suggest that early truncating mutations lead to a poor prognosis (classic Rett), while late truncating and missense mutations lead either to classic Rett or PSV. We hypothesize that a missense or late truncating mutation is necessary but not sufficient to produce a PSV, based on the presence of one (or more) modifier genes whose product may interact in a epistatic manner with MeCP2 protein. © 2001 Wiley‐Liss, Inc.     

Mutations in the NSDHL gene,encoding a 3β‐hydroxysteroid dehydrogenase,cause CHILD syndrome

We report for the first time that CHILD syndrome (MIM 308050), an X‐linked dominant, male‐lethal trait characterized by an inflammatory nevus with striking lateralization and strict midline demarcation, as well as ipsilateral hypoplasia of the body is caused by mutations in the gene NSDHL located at Xq28 (NAD(P)H steroid dehydrogenase‐like protein) encoding a 3β‐hydroxysteroid dehydrogenase functioning in the cholesterol biosynthetic pathway. SSCA and genomic sequence analysis of NSDHL identified in 6 patients with CHILD syndrome, including one boy as well as a mother and her daughter, mutations potentially impairing protein function. This phenotype is distinct from, but shares various clinical and biochemical findings with chondrodysplasia punctata (CDPX2, MIM 302960). CDPX2 is due to mutations affecting a Δ8‐Δ7 sterol isomerase (EBP, emopamil binding protein, at Xp11.22 ‐ p11.23) that functions downstream of NSDHL in a later step of cholesterol biosynthesis. EBP was unaffected in the patients analyzed by us demonstrating that CHILD syndrome and CDPX2 are not caused by allelic mutations. Two mouse X‐linked dominant male‐lethal traits, bare patches (Bpa) and striated (Str) had previously been associated with mutations in Nsdhl. They provide animal models for the study of CHILD syndrome, a further human condition due to mutations in a gene of the cholesterol synthesis pathway. Am. J. Med. Genet. 90:339–346, 2000. © 2000 Wiley‐Liss, Inc.     

Telomere Phenotypes in Females with Heterozygous Mutations in the Dyskeratosis Congenita 1 (DKC1) Gene

Dyskeratosis congenita (DC) is a telomere‐mediated syndrome defined by mucocutaneous features. The X‐linked mode of inheritance accounts for half the cases, and is thought to predominantly manifest in childhood as bone marrow failure. We identified two male probands who presented in the fifth decade with idiopathic pulmonary fibrosis and cancer. Their pedigrees displayed consecutively affected generations. Five of six females (83%) manifested mucocutaneous features of DC, and two had wound‐healing complications. No mutations in autosomal dominant telomere genes were present, but exome sequencing revealed novel variants in the X‐chromosome DKC1 gene that predicted missense mutations in conserved residues, p.Thr49Ser and p.Pro409Arg. Variants segregated with the telomere phenotype, and affected females were heterozygotes, showing skewed X‐inactivation. Telomerase RNA levels were compromised in cells from DKC1 mutation carriers, consistent with their pathogenic role. These findings indicate that females with heterozygous DKC1 mutations may be at increased risk for developing penetrant telomere phenotypes that, at times, may be associated with clinical morbidity.     

Discordance of oral–facial–digital syndrome type 1 in monozygotic twin girls

The oral–facial–digital syndrome type 1 (OFD1) includes limb, facial, intraoral malformations and the gene for the disorder was recently mapped to Xp22.3-p22.2. We report on monozygotic twin girls discordant for OFD1. Monozygosity is supported by placental pathology (monochorionic diamniotic) and molecular studies with probability of dizygosity <1 × 10⁻⁶. The affected twin has oral cavity abnormalities including median cleft lip, cleft palate, lobulated hamartomatous tongue, aberrant hyperplastic oral frenula, alveolar notches, and absent lateral incisors. Facial manifestations include telecanthus, hypoplastic alae nasi, and transient neonatal facial milia. The patient also has short and deviated fingers with partial cutaneous syndactyly. At 10 years, she has not had central nervous system or kidney problems. X-inactivation study revealed similar X-inactivation patterns in the lymphoblasts of both twins. We conclude that skewed X-inactivation is an unlikely cause for the discordance, which is more likely due to a postzygotic mutation in the affected twin. Am. J. Med. Genet. 86:269–273, 1999. © 1999 Wiley-Liss, Inc.     

An updated and upgraded L1CAM mutation database

The L1 syndrome is an X‐linked recessive disease caused by mutations in the L1CAM gene. To date more than 200 different mutations have been reported, scattered over the entire gene, about 35% being missense mutations. Although it is tempting to consider these missense mutations as being disease‐causing, one should be careful in drawing any firm conclusions, unless there is additional supporting information. This is in contrast to truncating mutations, which are always considered to be disease‐causing, unless they involve truncations close to the gene stop codon. In order to allow conclusions to be drawn on the disease‐causing nature of L1CAM (missense) mutations, we have updated and upgraded our LICAM mutation database with more pathogenicity data and clinical information collected from the literature or generated by our own research. As a result, the renewed database offers condensed scientific information, allowing conclusions to be drawn on the pathogenicity and severity of LICAM mutations based on multiple factors. The L1CAMMutation Database is at: www.l1cammutationdatabase.info . © 2009 Wiley‐Liss, Inc.     

Mohr syndrome (oro-facial-digital syndrome II) - a familial case with different phenotypic findings

We report on two male siblings with an oro-facial-digital syndrome. The parents and two other siblings, a boy and a girl, are unaffected. The clinical findings on the reported brothers were different. Patient 1 had typical oral, facial and digital anomalies plus hypoplastic genitalia and short limbs. Clinically he had marked hypotonia, convulsions and apneic episodes. He died shortly after birth. His brother, Patient 2, had OFD features with conductive hearing loss and normal psychomental development. He did not have syndactylous reduplication of the great toes, although the toes were disproportionately large. These two patients are classified as OFD type II-Mohr syndrome. Involvement of the central nervous system in OFD type II is noted. Different phenotypic findings could be explained as variable gene expressivity. The patients described here support the hypothesis that the clinical variability of the Mohr syndrome is even wider than previously thought.