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Abstract
Background Titin truncating variants (TTNtvs) have been associated with several forms of myopathies and/or cardiomyopathies. In homozygosity or in compound heterozygosity, they cause a wide spectrum of recessive phenotypes with a congenital or childhood onset. Most recessive phenotypes showing a congenital or childhood onset have been described in subjects carrying biallelic TTNtv in specific exons. Often karyotype or chromosomal microarray analyses are the only tests performed when prenatal anomalies are identified. Thereby, many cases caused by TTN defects might be missed in the diagnostic evaluations. In this study, we aimed to dissect the most severe end of the titinopathies spectrum.
Methods We performed a retrospective study analysing an international cohort of 93 published and 10 unpublished cases carrying biallelic TTNtv.
Results We identified recurrent clinical features showing a significant correlation with the genotype, including fetal akinesia (up to 62%), arthrogryposis (up to 85%), facial dysmorphisms (up to 73%), joint (up to 17%), bone (up to 22%) and heart anomalies (up to 27%) resembling complex, syndromic phenotypes.
Conclusion We suggest TTN to be carefully evaluated in any diagnostic process involving patients with these prenatal signs. This step will be essential to improve diagnostic performance, expand our knowledge and optimise prenatal genetic counselling.
- genetics, medical
- pediatrics
- neuromuscular diseases
- reproductive medicine
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Biallelic titin truncating variants (TTNtvs) often result in congenital myopathy, sometimes with severe developmental anomalies.
WHAT THIS STUDY ADDS
Over 65% of patients with a metatranscript-only TTNtv have dysmorphism such as micrognathia, high-arched palate, facial asymmetry, scaphocephaly, elongated face, low-set ears, multiple pterygia and thorax abnormalities.
Perinatal mortality is observed in around 40% of the most severe patients, mostly those carrying a metatranscript-only TTNtv or a TTNtv in exon 359.
The most severe forms of titinopathy go into differential diagnosis with syndromes such as Noonan syndrome, Escobar syndrome, congenital myasthenic syndromes, Larsen syndrome, Pena-Shokeir syndrome or fetal akinesia deformation sequence.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The present work helps clinicians in dealing with severe titinopathies and improves genetic conuselling.
We suggest TTN variants to be carefully evaluated in any diagnostic process involving patients with the mentioned signs.
Introduction
The TTN gene (Online Mendelian Inheritance in Man (OMIM) database (#188840) includes 364 exons (363 coding exons and the first non-coding exon) and codes for titin, the largest protein in our body.1 Titin forms the third myofilament structure spanning the sarcomere from the Z-disc to the M-band in both skeletal and cardiac muscle. The titin I-band portion works as a molecular spring, giving the muscle its elastic properties.1 2 Besides the mechanical properties, titin also has a role as a mechanosensor serving various signalling functions.3
Titin transcripts have a complex splicing pattern with several known isoforms.4 The canonical skeletal muscle isoform N2A is reported to include 312 exons and five isoforms are reported to have a cardiac expression. The longest of these is N2BA, which contains 311 exons.1 The theoretical isoform that includes all 363 coding exons is the virtual TTN metatranscript (NM_001267550).5 Exons not contained to any larger extent in adult skeletal or cardiac muscle isoforms are referred to as metatranscript-only exons (metaTTNtvs).6
Pathogenic TTN variants cause a wide range of skeletal myopathies and cardiomyopathies or combinations of both, varying by their mode of inheritance, age of onset, muscle involvement, severity and rate of progression.7–12
Some genotype–phenotype correlations in titinopathies, depending on the location of the variants, have been shown; for example, the adult-onset hereditary myopathy with early respiratory failure (OMIM #60369) is specifically caused by missense variants in exon 344, and the late-onset dominant distal myopathy, tibial muscular dystrophy (TMD, Udd myopathy), with heterozygous variants in the last exon 364.13 14
Similarly, a correlation between location of titin truncating variants (TTNtvs) and the clinical manifestation of recessive titinopathies has been proposed.6 15 The specific pathomechanism caused by variants resulting in premature stop codons in the I-band and A-band has not been fully clarified, although we still lack evidence of the skeletal muscle expression of truncated protein encoded by these alleles.6 On the contrary, premature stop codons in the M-band (last six exons 359–364) result in a near-full length protein that is probably able to integrate into the sarcomere. There is a clear relationship between the position of the truncation in the M-band and the phenotype in patients. Very terminal biallelic truncating variants in the last two exons 363 and 364 cause juvenile-early adult onset recessive distal titinopathy.16 On the contrary, patients carrying a TTNtv at the beginning of the M-band (exon 359) in homozygosity or in compound heterozygosity with a second TTNtv in a canonical exon out of the M-band have a congenital onset resulting in neonatal hypotonia and leading to a severe form of congenital titinopathy.6 17 18 Finally, a truncating variant in a metaTTNtv in homozygosity or in compound heterozygosity with another TTNtv causes arthrogryposis congenita and severe axial hypotonia as a form of congenital amyoplasia.15 19 20
Our study, analysing clinical and molecular data from a cohort of novel and previously described recessive titinopathy cases with congenital anomalies or dysmorphisms, proves that biallelic titin pathogenic variants cause recognisable fetal and developmental defects. All the newly reported patients show a severe prenatal or congenital phenotype leading to fetal, perinatal or infantile death, thus describing the most severe end of the titinopathies.
Patients and methods
Recruitment
We collected either cases from obstetrical and neonatology units of different international hospitals or cases that have been brought to our attention by direct request for counselling.
Clinical feature analysis
The cases have been clinically assessed by gynaecologists experienced in prenatal diagnostics. In four cases, autopsy was performed after voluntary abortion or fetal death (F4-II.1, F4-II.2, F6-II.3 and F6-II.4). Four infants were born alive (F1-II.1, F3-III.1, F3-III.2 and F5-II.1); three were admitted to the intensive care unit and died shortly after during hospital admission. One infant (F5-II.1) survived until the age of 5 years and remained under clinical follow-up with a paediatrician and a neurologist.
Molecular genetic studies
Probands’ DNA was analysed using gene panels or exome sequencing (ES). Sequencing data were analysed using standard bioinformatic pipelines aiming at the identification of single-nucleotide variants, small insertions or deletion (indels). In all cases, segregation analysis (via Sanger or massive parallel sequencing) was performed to confirm the phase of the variants.
All the variants had been evaluated following the American College of Medical Genetics (ACMG) and the Association for Molecular Pathology (AMP) criteria for variant interpretation using the default settings in Varsome V.5.6 (on 14 October 2022).21 Variants are reported in the article using the inferred meta-transcript NM_001267550.1.
Previously reported cases
Medical literature was searched using PubMed (search terms: titin, TTN, titinopathy, congenital myopathy and muscular dystrophy; last search undertaken on 1 October 2022). We included previously reported patients with antenatal, congenital, infantile or childhood-onset (<2 years of age) recessive titinopathy carrying biallelic TTNtv classified as pathogenic or likely pathogenic according to current guidelines for whom molecular and clinical findings were available (n=93 cases) (online supplemental table 1).
Supplemental material
Results
We reported 10 cases from six unrelated families (table 1) showing different TTNtv combinations. Four cases carried a heterozygous variant in exon 359 in combination with a TTNtv in a canonical exon (Z-disk, I-band or A-band); one case was a compound heterozygous for two TTNtvs in exon 359, and five cases carried a TTNtv in a metaTTNtv in combination with a TTNtv in a canonical exon (A-band). Molecular and clinical details of these 10 cases are summarised in table 1.
Summarised genotypes and phenotypes of the 10 unpublished cases
Family history and first-level analyses
Family history, as depicted by the pedigrees in online supplemental file 2, was negative in all the cases, except for one grandparent (family 3) who was reported to have dilated cardiomyopathy, although he was not genetically investigated.
Supplemental material
In three out of six families, ES of the trio was not the first-tier test. In two cases (families 3 and 6), a sequencing test covering titin was performed following the reoccurrence of the disease in a second sibling. All the other genetic analyses performed (karyotype, Comparative Genomic Hybridization (CGH)-array and in one case also SMN1 sequencing) gave normal results. No other clinically relevant disease-causing variants were identified by trio sequencing analysis.
Unreported cases with at least one metatranscript-only variant
All five patients carrying a TTNtv in a metaTTNtv died in uterus spontaneously or following a voluntary abortion procedure due to severe ultrasound-detected abnormalities (n=2), approximately between the 25 and 35 weeks of gestation. In all cases, severe signs such as fetal akinesia and limb contractures were found at ultrasound examination. In particular, in case F4-II.2, abnormal villous maturation was reported at autopsy, in addition to the typical arthrogryposis multiplex phenotype. In case F6-II.3, ultrasound examination at 21 weeks of gestation showed abnormalities of THE corpus callosum, absent movements on prolonged observation, upper and lower limbs in constant flexion, immobile extremities and flattened thorax anteriorly with normal thorax:abdomen ratio. In case F6-II.4 (figure 1), severe contractures of the upper and lower limbs were found in two different ultrasound examinations at 16 and 20 weeks. All metatranscript-only cases showed severe muscle hypoplasia, skeletal muscle damage and rarefaction of muscle fibres at the anatomopathological examination.
Ultrasound examination images of cases F6-II.3 (first three images) and F6-II.4 (last three images). Abnormalities of the corpus callosum, placenta previa and limb in case F6-II.3 (A–C) and severe arthrogryposis in case F6-II.4 (D–F) can be observed.
Unreported cases with an exon 359 truncating variant
Four cases from three unrelated families (families 1, 2 and 3) with a combination of TTNtv in exon 359 and a TTNtv in a canonical exon showed severe abnormalities on ultrasound examination, including hydrops fetalis and polyhydramnios. One fetus (F2-II.1) died in uterus at 35 weeks of gestation, while two others (F3-II.1 and F3-II.2) were born preterm (35 and 36 weeks, respectively), and one was born at early term (F1-II.1). They all presented with arthrogryposis, one of them joint dislocation, and two of them showed undeveloped lungs. No congenital cardiac defect was reported in our cohort. Only the patient carrying two TTNtvs in exon 359 (F5-II.1), who survived until childhood, developed dilated cardiomyopathy during infancy. All the presented cases (F1-II.1, F3-II.1, F3-II.2 and F5-II.1) with at least one TTNtv in exon 359 who were born alive died of respiratory failure.
Clinical features of antenatal and congenital titinopathies: evidence in a wider context
Ninety-three recessive cases due to biallelic TTNtv with congenital or early-onset (<2 years of age) titinopathy have been reported in the literature (online supplemental table 1). For the purpose of this paper, we considered only those cases for which molecular and clinical findings were available. In addition, we added to the analysis the 10 new cases of recessive titinopathies described previously, to refine a tentative genotype–phenotype correlation.
Of the 103 analysed cases, 63 (61%) were alive at the time of data collection. For a proper analysis of the antenatal and perinatal signs and symptoms, we grouped and analysed cases according to their genotype.
Evidence on metaTTNtv
Thirteen cases have biallelic nonsense or indels causing a premature stop codon in metaTTNtvs. Twenty cases have a nonsense or an indel causing a frameshift in a metatranscript-only in compound heterozygosity with a nonsense or an indel variant causing a premature stop codon in a canonical exon. Overall, metaTTNtv cases (group A, online supplemental file 1) show the lowest survival rate in the prenatal and perinatal period in the entire cohort, as only 14 out of 33 patients (42%) were alive 6 months post partum (figure 2). This group also shows a consistent prevalence of reported abnormal prenatal signs such as fetal akinesia (55%, n=18), polyhydramnios (18%, n=6) and fetal hydrops (18%, n=6) (figures 3 and 4). Micrognathia, retrognathia, facial anomalies and other dysmorphisms have been reported in 45% (n=15) of the cases. At birth, almost all of them (85%, n=28) presented with severe contractures, especially in distal limbs, and they were described as having arthrogryposis multiplex congenita or as distal arthrogryposis. A large proportion of live infants also had generalised hypotonia (78%, n=18), respiratory difficulties requiring intubation (35%, n=8) and feeding difficulties requiring nasogastric tube feeding (30%, n=7); some of them (n=9) died after a few weeks mainly of respiratory insufficiency. Also, 22% of the infants (n=5) reported congenital bone fractures at birth. Only one case reported unspecified cardiac anomalies at birth. Two infants who died after delivery showed hypoplastic hearts at autopsy. The mean gestational age at prenatal death was 27 weeks, while the mean age at postnatal death was 5 weeks of life approximately. The mean age at last evaluation for surviving patients was 10 years.
Description of the main signs suggestive of prenatal titinopathy in fetuses and infants. Survival rates in percentages are shown for the following groups: group A, metaTTNtv; group B, exon 359 TTNtv; group D, canonical TTNtv with splice variant; group E, metaTTNtv with splice variant. In-depth descriptions of genotypes are provided in the article. Created with BioRender.com. CNS, central nervous system; metaTTNtv, metatranscript-only exon; TTNtv, titin truncating variant.
Analysis of the most frequent clinical findings according to genotype: group A, metaTTNtv (at least one metaTTNtv and no splice variants); group B, exon 359 TTNtv (at least one TTNtv in exon 359, no metaTTNtv, no splice variants and no other M-band TTNtv); group C, exon 360–363 TTNtv (at least one TTNtv in M-band exons 360–363); group D, canonical TTNtv with splice variant (ie, at least one splice variant and no metaTTNtv); group E, metaTTNtv with splice variant (at least one metaTTNtv and one splice variant). In-depth descriptions of genotypes are provided in the article. χ2 test was performed and p values are displayed next to the clinical signs when there is significant difference between the groups. *P≤0.05, ***P≤0.001. metaTTNtv, metatranscript-only exon; TTNtv, titin truncating variant.
Analysis of the less frequent clinical findings according to the genotype. Chi-square test wasperformed and p-values have been displayed next to the clinical signs when there is significant differencebetween the groups. *P≤0.05,
Evidence on TTNtv in exon 359
Seventeen patients carry a nonsense or an indel causing a frameshift in exon 359 in homozygosity or in compound heterozygosity with second variant in a canonical exon causing a premature stop codon out of the M-band (group B, online supplemental file 1). Of these, three cases (18%) died in uterus, two (12%) by therapeutic abortion, one (6%) for miscarriage at the 35th week. Among the survived cases, five died (31%) up to 6 months after birth, while one (F5-II.2, the carrier of the homozygous variant in exon 359 described in this paper) died in early childhood (5 years old) due to dilated cardiomyopathy (DCM). Thirteen cases (76%) reported limb contractures, but in two of them, the onset was clearly postnatal. Overall, the mean gestational age at prenatal death was 35 weeks, while the mean age at postnatal death was less than 1 day post partum, with the exception of F5-II.2 (see previous discussion). The mean age at last evaluation for surviving patients was 10 years.
Two cases carrying out-of-frame deletions in exon 359 in compound heterozygosity with a metaTTNtv have been described (group A, online supplemental file 1). They presented with hypotonia at birth, and they were both alive at the data collection (last examination at 14 and 2 years, respectively). The 14-year-old patient developed contractures after birth.
Evidence on TTNtv in exons 360–363
Ten previously published cases reported two out-of-frame indels in exons 360–363 or one indel in exon 360–363 in compound heterozygosity with a TTNtv in a canonical exon, mainly in the M-band (group C, online supplemental file 1). They had mostly a childhood onset (at 1–2 years approximately), and five of them (50%) died between 8 years and 19 years due to progressive DCM. The mean age at death overall was 15 years, while the mean age at last evaluation for surviving patients was 17.5 years. Prenatal signs were reported in a single case. Half of them developed joint contractures after birth, as shown in figure 3.
Evidence on combinations of TTNtv including splice variants
Fifteen patients (group D) have biallelic splice variants affecting canonical exons (n=3) or a monoallelic splice variant affecting the expression of a canonical exon and a second nonsense or indel variant in canonical exons (n=12). Twenty-six patients (group E) have a splice variant either affecting the expression of a metaTTNtv—for example, the recurrent splice-site variant c.39 974-11T>G in intron 213—or of a canonical exon with a second nonsense variant in metaTTNtv (group E). The genotype with a splice variant is associated with lower lethality. There was no fetal death registered in groups D and E, while three patients died in the peripartum. Interestingly, one of them was the recipient monozygotic twin in the setting of twin-to-twin transfusion syndrome and died from severe cardiac hypertrophy soon after birth, while the other twin survived.22 Two cases carrying out-of-frame deletion in exon 359 in compound heterozygosity with a splice variant in a canonical exon have also been described (group F, online supplemental file 1).
The occurrence of the other signs and symptoms is summarised in figures 3 and 4.
Prevalence of dilated cardiomyopathy
Thirty-four cases out of 103 carried biallelic TTNtv predicted to impact both N2BA and N2B cardiac isoforms: 18 of them (53%) were reported to have cardiac involvement. In 11 cases, DCM became overt in childhood or at juvenile age, while 6 cases were reported to have other cardiac congenital anomalies, such as atrial septal aneurysm, atrial septal defects, large outlet and atypical muscular ventricular septal defect, left ventricular non-compaction and left ventricular dysfunction/hypocontractility. In 16 of the 34 cases, cardiac signs or symptoms were excluded (n=6) or not reported (n=10).
Discussion
The clinical spectrum of titinopathies has expanded considerably in recent years, with additional evidence of a severe end of the phenotypical spectrum caused by biallelic combinations of truncating variants. Some of these forms begin prenatally; others are recognised at birth or develop postnatally.3 12 23–25 According to the definitions reported in Human Phenotype Ontology (https://hpo.jax.org/app/), the term ‘congenital’ should be ‘used for phenotypical abnormalities or diseases initially observed at the time of birth’.26 For abnormalities observed prior to birth (eg, by fetal ultrasound), the term ‘antenatal onset’ (HP:0030674) would be more appropriate. In contrast, ‘infantile onset’ (HP:0003593) refers to ‘onset of signs or symptoms of the disease between 28 days to 1 year of life’, while ‘childhood onset’ (HP:0011463) refers to ‘onset of disease at the age of between 1 and 5 years’. Since a standardised use of terminology may facilitate the comparison between published cases as well as the understanding of the genotype–phenotype correlation, we have adopted these definitions regarding early-onset titinopathies and we encourage a standardisation of the nomenclature for TTN-related diseases that reflects the HPO terminology.
Although it is still difficult to delineate proper genotype–phenotype correlations, the antenatal cases reported here, together with the previously reported ones, highlight some interesting recurrent clinical findings.
Fetuses with metatranscript-only variants usually display a severe, syndromic-like phenotype, recognisable by prenatal ultrasound examination. They have the highest rate of fetal lethality and developmental anomalies, as reported in figures 2–4. The severe clinical findings in the cases with the metatranscript-only variants include joint, bone and heart anomalies, such as congenital bone fractures and hypoplastic heart. These findings are in keeping with the hypothesis that the metatranscript (or probably several transcripts including a number of the so-called meta-exons) may serve as a scaffold during the sarcomere development and that its disruption leads to severe defects in the development of the musculoskeletal system with secondary consequences for other structures. Three of them had anomalies also of the central nervous system reported by ultrasound examination, such as dysgenesis of the corpus callosum and abnormal liquor volume. One case who died in the peripartum presented anomalies of cerebral sulci. Also, in 10 cases, joint hypermobility was detected after birth (figure 3), although the cause of this sign and its correlation with impaired sarcomere development are still to be clarified.
Interestingly, seven patients with a TTNtv in the M-band (exons 359–364) developed postnatal contractures, suggesting a more progressive clinical course after birth. This is opposite to what was observed in patients with variants in the metatranscript, who more often have antenatal arthrogryposis multiplex congenita and may then present a degree of improvement in postnatal life.
While the clinical interpretation of metaTTNtv has been well defined in recent years, the interpretation of TTNtv in exon 359 remains challenging. Indeed, it is a very large exon, and the precise starting point of the M-band has not yet been unambiguously defined. Moreover, there are only few cases reported in the literature, and for most of them, the clinical description is incomplete, not allowing to draw final conclusions. In general, we see that patients with one TTNtv in exon 359 in compound heterozygosity with a TTNtv in a canonical exon may have a severe antenatal or congenital onset; some of them died after delivery, while others are alive in their infancy and young age (figure 2). While infants with one TTNtv in exon 359 may have congenital cardiac abnormalities, patients with two biallelic variants in exon 359 (n=6) have a high rate of DCM prevalence with a later onset, as half of the reported cases (n=3) died of heart failure in childhood or in their 20s, similarly to what happens in patients with biallelic TTNtv in exons 360–363.
As expected, combinations of TTNtv with at least one splice variant affecting the expression of a canonical exon (group D) were associated with less severe phenotypes. In these patients, the alleles with the splice variant produce a slightly altered transcript and protein. In general, patients carrying at least one splice variant show a lower lethality ratio (figure 2).27 A splice variant in compound heterozygosity with a TTNtv in a canonical exon is most probably in-frame (total absence of titin, due to two null alleles, is incompatible with embryonic development). Similarly, when two splice variants affecting a canonical exon are present, at least one of them is expected to be in-frame. However, studies on patients’ muscle tissues would be needed to determine the effects of any of these variants on splicing on the transcripts and, thereby, on the protein.
Interestingly, regarding family history, none of the parents who carry a TTNtv in a cardiac exon are reported to show clinically overt cardiomyopathy at the time of examinations. Nevertheless, in our cohort, following the recent ACMG guidelines, the proband’s parents carrying heterozygous TTNtv in exons expressed in the titin cardiac isoforms were referred to genetic counselling. In the case of family 6, we know that cardiological evaluation with echocardiography was prescribed but not yet performed; however, the proband’s father, who carries a TTNtv in A-band, is reported to play sports regularly and to have been assessed as healthy by previous cardiological evaluation. It must be emphasised that in subjects in whom a truncating variant in titin is found as an incidental finding, the penetrance is far from being complete, and it is reasonably lower than the penetrance reported for patients with a positive family history of cardiac diseases.28 29
Together with our knowledge of the titinopathies spectrum, the number of clinicians involved in the diagnosis and management of these not-so-rare diseases is constantly growing.22 30 Ever since TMD was discovered,31 it has been mainly the neurologists who dealt with titinopathies. In recent years, following the publication of the first cases of congenital titinopathies, child neurologists, neonatologists and paediatricians have been increasingly involved. The present study highlights that congenital phenotypes present with a high rate of typical signs in the antenatal period, in particular facial dysmorphisms (micrognathia, high-arched palate, facial asymmetry, scaphocephaly, elongated face, low-set ears, multiple pterygia and thorax abnormalities), arthrogryposis, bone fractures and heart anomalies. Their identification and the assessment of their prevalence opens the possibility of early detection, higher diagnostic rate and more in-depth investigations of the natural history of the disease. Probably, we are still missing the most severe end spectrum of titinopathies, as we are used to studying fetuses from late miscarriages or dead infants, while only few investigations are usually performed on early miscarriages. Moreover, prenatal tests often do not include TTN sequencing.32–34 Titin’s involvement in prenatal and congenital phenotypes has similarities with that of severe variants in nebulin (NEB), a known sarcomeric protein. Recessive truncating mutations in NEB may cause arthrogryposis multiplex congenita, type 6 (OMIM #619334), resulting in a clinical phenotype that is very similar to that observed in the severe cases of recessive titinopathies. Noteworthily, titin and NEB act together as ‘molecular rulers’, respectively, of the thick and the thin filaments of the sarcomere.35
Some recent studies focused on the ethical implications of a genetic diagnosis in critically unwell newborns and fetal cases with major ultrasound findings.36 37 In line with those reflections, although attention must be paid to offering proper genetic counselling, we believe that a prompt diagnosis can be of great benefit to the family, allowing the parents to face the future and avoid repeated negative pregnancy experiences that could have major psychological and physical repercussions.38 39
We are aware that our research may have some limitations. First of all, prenatal ultrasound examination is operator-dependent, and thus the prevalence of antenatal signs may be influenced by reporting bias.40 Also, the already published cases may be not uniformly described, as some papers were more clinically detailed than others; instead, unpublished cases were accurately detailed, but they still do not allow us to draw further genotype–phenotype conclusions. Thus, a prospective study involving many international centres would be needed to have more in-depth clinical information about severe antenatal and congenital titinopathies. Most importantly, we still have a limited knowledge of the exon usage and of the specific isoforms expressed in different prenatal and postnatal muscles, and similarly, we lack an in-depth understanding of all the effects of truncating variants on the protein and on different transcripts.
Conclusion
Severe recessive titinopathies, mainly caused by truncating variants in metaTTNtvs or in exon 359, have antenatal signs resembling a syndromic phenotype, affecting not only the skeletal muscle but also bone, heart and other organs, with a quite high rate of dysmorphisms. They can therefore go in differential diagnosis with several forms of arthrogryposis multiplex congenita as well as with other developmental syndromes (eg, Noonan syndrome, Escobar syndrome, congenital myasthenic syndromes, Larsen syndrome, Pena-Shokeir syndrome or fetal akinesia deformation sequence). It is thus crucial to raise awareness that TTNtv does cause not only myopathies but also complex phenotypes, and that antenatal and congenital titinopathies need to be recognised in different clinical settings. As a consequence, titin should be included among the genes to be analysed in antenatal cases with arthrogryposis, neonatal hypotonia and the previously discussed signs and symptoms.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by the institutional review board of Helsingin Yliopistollinen Sairaala, Hospital District of Helsinki and Uusimaa (HUS:195/13/03/00/11). The participants gave informed consent to participate in the study before taking part. The study was performed in accordance with the Declaration of Helsinki.
Acknowledgments
The authors thank all the patients and family members for their cooperation and all the clinicians for collecting patient data.
References
Supplementary materials
Supplementary Data
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Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
MS and BU contributed equally.
Contributors Conceptualisation: MS and MFDF; data curation: MFDF; data analysis and writing (original draft): MFDF and VL; patient recruitment and phenotypical characterisation: EG, AB, TH, MM, MJ, MI, LS, PD'O, GCCC and BU; supervision and writing (review and editing): MS and BU. MFDF and MS are also the guarantors.
Funding MS received funding from the Academy of Finland and Sydantutkimussaatio. BU received funding from the Academy of Finland and the European Joint Programme for Rare Disease.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.