Matias Wagner1,2,3, Dominik S Westphal1,2, Iris Hannibal4, Johannes A. Mayr5, Tim M. Strom1,2, Thomas Meitinger1,2, Holger Prokisch1,2, Saskia B. Wortmann1,2,5
1. Institute of Human Genetics, Technical University Munich, Munich, Germany;
2. Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany;
3. Institute of Neurogenomics, Helmholtz Zentrum Munich, Neuherberg, Germany
4. Dr. von Hauner Children’s Hospital, Ludwig-Maximilians University, Munich, Germany
5. Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria
Biallelic mutations in KIAA0586 have been related to Joubert syndrome (JBTS) 23 and as the most frequent disease causing variant c.428del (p.Arg143Lysfs*4) was identified.1 However, the allele frequency of 0.003117 and two homozygotes in the gnomAD dataset as well as additional reports of healthy carriers have questioned the variant’s pathogenicity.2, 3 Pauli et al. have recently hypothesized that c.428del is a hypomorphic allele which is only causing JBTS in compound heterozygosity with other mutations.
In 15,000 in-house exome data sets, we have identified three individuals harboring c.428del in a homozygous state. In two, we identified other variants sufficiently explaining the phenotype: In a 6 year old girl with global developmental delay and progressive myoclonic astatic epilepsy, we identified a de novo variant c.2683del, p.Ser895Le...
Matias Wagner1,2,3, Dominik S Westphal1,2, Iris Hannibal4, Johannes A. Mayr5, Tim M. Strom1,2, Thomas Meitinger1,2, Holger Prokisch1,2, Saskia B. Wortmann1,2,5
1. Institute of Human Genetics, Technical University Munich, Munich, Germany;
2. Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany;
3. Institute of Neurogenomics, Helmholtz Zentrum Munich, Neuherberg, Germany
4. Dr. von Hauner Children’s Hospital, Ludwig-Maximilians University, Munich, Germany
5. Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria
Biallelic mutations in KIAA0586 have been related to Joubert syndrome (JBTS) 23 and as the most frequent disease causing variant c.428del (p.Arg143Lysfs*4) was identified.1 However, the allele frequency of 0.003117 and two homozygotes in the gnomAD dataset as well as additional reports of healthy carriers have questioned the variant’s pathogenicity.2, 3 Pauli et al. have recently hypothesized that c.428del is a hypomorphic allele which is only causing JBTS in compound heterozygosity with other mutations.
In 15,000 in-house exome data sets, we have identified three individuals harboring c.428del in a homozygous state. In two, we identified other variants sufficiently explaining the phenotype: In a 6 year old girl with global developmental delay and progressive myoclonic astatic epilepsy, we identified a de novo variant c.2683del, p.Ser895Leufs*14 in KIAA2022 (NM_001008537.2, MIM#300912: mental retardation 98). In a 56 year old male patient from a large family with X-linked mental retardation, a hemizygous missense variant in FRMPD4 (NM_014728.3): c.41861G>T, p.Asp621Tyr was identified. In the third case, a 5 year old boy with medically unexplained isolated fatigue we did not identify other variants than c.428del in KIAA0586.
However, in a 3 year old male with global delays, truncal hypotonia, ataxia and eye movement disorders we identified the variant c.428del in compound heterozygosity with c.863_864del, p.Gln288Argfs*7 (NM_014749.3). As the clinical findings resemble the core phenotype of JBTS23, we consider the combination of these variants causal for the patient’s condition.4
Analysis of RNA sequencing data from two heterozygous carriers indicates that mutant transcripts escape nonsense mediated decay. Residual function of the c.428del KIAA0586 allele most likely originates from the use of an alternative start codon (Supplementary figure).
These findings further strengthen the hypothesis of Pauli et al. that c.428del is indeed a hypomorphic allele which is only disease causing in trans with a loss of function mutation.
References
1. Bachmann-Gagescu R, et al. KIAA0586 is Mutated in Joubert Syndrome. Human mutation 36, 831-835 (2015).
2. Pauli S, et al. Homozygosity for the c.428delG variant in KIAA0586 in a healthy individual: implications for molecular testing in patients with Joubert syndrome. Journal of medical genetics, (2018).
3. Sulem P, et al. Identification of a large set of rare complete human knockouts. Nature genetics 47, 448-452 (2015).
4. Bachmann-Gagescu R, et al. Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity. Journal of medical genetics 52, 514-522 (2015).
in their recent study Arends and colleagues demonstrate a significant 2.8-fold increased risk for the formation of neutralizing anti-drug antibodies (ADA) in male patients with Fabry disease (FD) when treated with agalsidase-beta (1.0 mg/kg every other week) compared to agalsidase-alfa (0.2 mg/kg every other week).[1] Interestingly, Rombach and colleagues and later Smid and colleagues reported no significant differences in a humoral response, when using an identical dosage of 0.2 mg/kg for both drugs. [2,3] Hence, the 5-fold higher dosage of agalsidase-beta and not the compound itself seems to be an important trigger for antibody formation. However, none of the studies determined the cross reactive immunological status, which is crucial for the risk of a humoral response. The subgroup analysis of patients with ADAs by Arends and colleagues also revealed a better biochemical response to agalsidase-beta at 1.0 mg/kg in terms of decreasing lyso-Gb3 levels.[1] The authors propose that a saturation of antibody titers due to the 5-fold higher dosage might lead to the observed effect. In this respect, we recently demonstrated that antibodies can be supersaturated and that appropriate (i.e. individually optimized) enzyme dosages can overcome ADA titers already during infusions, which may result in improved patients’ outcome.[4] However, in the same study, we also demonstrated that even in patients treated with low-dose enzyme replacement therapy ADA titers can...
in their recent study Arends and colleagues demonstrate a significant 2.8-fold increased risk for the formation of neutralizing anti-drug antibodies (ADA) in male patients with Fabry disease (FD) when treated with agalsidase-beta (1.0 mg/kg every other week) compared to agalsidase-alfa (0.2 mg/kg every other week).[1] Interestingly, Rombach and colleagues and later Smid and colleagues reported no significant differences in a humoral response, when using an identical dosage of 0.2 mg/kg for both drugs. [2,3] Hence, the 5-fold higher dosage of agalsidase-beta and not the compound itself seems to be an important trigger for antibody formation. However, none of the studies determined the cross reactive immunological status, which is crucial for the risk of a humoral response. The subgroup analysis of patients with ADAs by Arends and colleagues also revealed a better biochemical response to agalsidase-beta at 1.0 mg/kg in terms of decreasing lyso-Gb3 levels.[1] The authors propose that a saturation of antibody titers due to the 5-fold higher dosage might lead to the observed effect. In this respect, we recently demonstrated that antibodies can be supersaturated and that appropriate (i.e. individually optimized) enzyme dosages can overcome ADA titers already during infusions, which may result in improved patients’ outcome.[4] However, in the same study, we also demonstrated that even in patients treated with low-dose enzyme replacement therapy ADA titers can be supersaturated.[4] Therefore, we conclude that assessments of individual antibody titers should be performed to determine optimal enzyme dosages for supersaturation of present antibodies and thus probably resulting in higher therapy efficiency and improved disease progression.
1. Arends M, Biegstraaten M, Wanner C, Sirrs S, Mehta A, Elliott PM, Oder D, Watkinson OT, Bichet DG, Khan A, Iwanochko M, Vaz FM, van Kuilenburg ABP, West ML, Hughes DA, Hollak CEM. Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study. J Med Genet. 2018 Feb 7. doi: 10.1136/jmedgenet-2017-104863. [Epub ahead of print]
2. Rombach SM, Aerts JM, Poorthuis BJ, Groener JE, Donker-Koopman W, Hendriks E, Mirzaian M, Kuiper S, Wijburg FA, Hollak CE, Linthorst GE. Long-term effect of antibodies against infused alpha-galactosidase A in Fabry disease on plasma and urinary (lyso)Gb3 reduction and treatment outcome. PLoS One. 2012;7:e47805.
3. Smid BE, Hoogendijk SL, Wijburg FA, et al. A revised home treatment algorithm for Fabry disease: influence of antibody formation. Mol Genet Metab 2013;108:132-7.
4. Lenders M, Schmitz B, Brand SM, Foell D, Brand E. Characterization of drug-neutralizing antibodies in patients with Fabry disease during infusion. J Allergy Clin Immunol. 2018 Feb 5. doi: 10.1016/j.jaci.2017.12.1001. [Epub ahead of print]
We read with interest the case series of 6 patients with Bohring-Opitz syndrome (BOS) phenotype who were found to have autosomal recessive truncating mutations in the KLHL7 gene[1]. The purpose of this letter is to report a novel truncating mutation in KLHL7, and to expand the phenotype of recessive KLHL7 variants.
Our patient is a now 32-month-old male of Guatemalan descent who was born at 37 weeks’ gestation after a pregnancy complicated by fetal hydronephrosis, IUGR, and maternal hypertension. Birthweight was 2.5 kg, and he failed the neonatal hearing screen bilaterally. He was admitted to the NICU for desaturation events and was treated with supplemental oxygen. Polysomnography was performed at 4 weeks of life and identified central sleep apnea, with a central apnea index of 11 events/hour and no significant obstructive component. PHOX2B testing ruled out congenital central hypoventilation syndrome. A brain MRI demonstrated hypoplasia of the corpus callosum, delayed myelination, pontine hypoplasia, and subependymal nodular heterotopia along the lateral ventricles. A chromosome microarray was negative for deletions and duplications, though it indicated multiple areas of homozygosity (combined total length ~24 Mb).
He demonstrated some neck control at 3 months of age, and at age 2 years was able to roll for mobility. He remains nonverbal, tracheosteomy- and gastrostomy tube-dependent. Kyphoscoliosis was noted at 11 months of age and is progressing. He is also...
We read with interest the case series of 6 patients with Bohring-Opitz syndrome (BOS) phenotype who were found to have autosomal recessive truncating mutations in the KLHL7 gene[1]. The purpose of this letter is to report a novel truncating mutation in KLHL7, and to expand the phenotype of recessive KLHL7 variants.
Our patient is a now 32-month-old male of Guatemalan descent who was born at 37 weeks’ gestation after a pregnancy complicated by fetal hydronephrosis, IUGR, and maternal hypertension. Birthweight was 2.5 kg, and he failed the neonatal hearing screen bilaterally. He was admitted to the NICU for desaturation events and was treated with supplemental oxygen. Polysomnography was performed at 4 weeks of life and identified central sleep apnea, with a central apnea index of 11 events/hour and no significant obstructive component. PHOX2B testing ruled out congenital central hypoventilation syndrome. A brain MRI demonstrated hypoplasia of the corpus callosum, delayed myelination, pontine hypoplasia, and subependymal nodular heterotopia along the lateral ventricles. A chromosome microarray was negative for deletions and duplications, though it indicated multiple areas of homozygosity (combined total length ~24 Mb).
He demonstrated some neck control at 3 months of age, and at age 2 years was able to roll for mobility. He remains nonverbal, tracheosteomy- and gastrostomy tube-dependent. Kyphoscoliosis was noted at 11 months of age and is progressing. He is also noted to have a secundum atrial septal defect, and right-sided grade 4 vesicoureteral reflux with reflux nephropathy and hydroureter. An ophthalmology evaluation at age 16 months revealed optic nerve pallor and enlarged optic nerve cups (cup-to-disc ratio 0.6), but no retinal findings. His physical exam is notable for microcephaly (-2 SD), a prominent forehead, low-set ears with uplifted lobes, micrognathia, high palate, bilateral knee and elbow contractures, wrist flexion with ulnar deviation of the wrists and fingers (“BOS posture”), long fingers with camptodactyly and middle finger in palm deformity, prominent heels, a right hydrocele and buried penis, central hypotonia with appendicular hypertonia, and bilateral ankle clonus.
Whole exome sequencing revealed a novel truncating homozygous mutation in the KLHL7 gene (NM_001031710.2:c.976C>T, p.Arg326*). Parents were each found to carry one copy of the variant.
We report our patient with many features of patients with KLHL7-related disorder, including IUGR, optic nerve abnormalities, brain abnormalities, central hypotonia, joint contractures,, scoliosis, feeding difficulty and genitourinary and cardiac differences, features overlapping the Crisponi/CISS1-like phenotype and BOS-like phenotype. Our patient was also found to have severe central sleep apnea, well documented by polysomnography. We thus expand the phenotypic and mutational spectrum of KLHL7-related disorders.
References:
1 Bruel A-L, Bigoni S, Kennedy J, et al. Expanding the clinical spectrum of recessive truncating mutations of KLHL7 to a Bohring-Opitz-like phenotype. J Med Genet 2017;54:830–5.
We read with interest the case series of 12 patients with loss-of-function denovo heterozygous mutations in ASXL3, reported by Balasubramanian et al in August 2017. We want to report on a further case of Bainbridge – Ropers Syndrome (BRS) seen in our department. The purpose of this letter is two-fold. The first is to report on the mild features of BRS and the second is to expand the spectrum of features in BRS reiterating that all cases may not have severe features.
The proband is now 7 years old who first presented to the genetic services at the age of 3 years with global developmental delay and epilepsy. He is the first child of non-consanguineous healthy parent of Indian heritage. There is no family history of learning difficulties, autism or developmental delay.
He was born after a normal pregnancy by LSCS for prolonged labour with a birth weight of 2.9kg at term. He started sitting independently at 16 months and walking at 22 months. He has speech and language delay. He initially presented with 2 episodes of febrile convulsions; the first lasting 1 minute and second 10 minutes, at 3 and a half years of age. He then went on to develop tonic- clonic seizures thereafter all requiring hospital admission. He was recruited to the deciphering development disorder project (DDD) and on whole exome sequencing detected two variants in ASXL3 and DMD gene respectively.
This variant is predicted to cause a frameshift mutation resulting in a premature terminat...
We read with interest the case series of 12 patients with loss-of-function denovo heterozygous mutations in ASXL3, reported by Balasubramanian et al in August 2017. We want to report on a further case of Bainbridge – Ropers Syndrome (BRS) seen in our department. The purpose of this letter is two-fold. The first is to report on the mild features of BRS and the second is to expand the spectrum of features in BRS reiterating that all cases may not have severe features.
The proband is now 7 years old who first presented to the genetic services at the age of 3 years with global developmental delay and epilepsy. He is the first child of non-consanguineous healthy parent of Indian heritage. There is no family history of learning difficulties, autism or developmental delay.
He was born after a normal pregnancy by LSCS for prolonged labour with a birth weight of 2.9kg at term. He started sitting independently at 16 months and walking at 22 months. He has speech and language delay. He initially presented with 2 episodes of febrile convulsions; the first lasting 1 minute and second 10 minutes, at 3 and a half years of age. He then went on to develop tonic- clonic seizures thereafter all requiring hospital admission. He was recruited to the deciphering development disorder project (DDD) and on whole exome sequencing detected two variants in ASXL3 and DMD gene respectively.
This variant is predicted to cause a frameshift mutation resulting in a premature termination codon in exon 12 of ASXL3. There are no other reports of this variant in any databases or in the published literature. Loss of function variant in ASXL3 have been reported in patients with Bainbridge – Ropers Syndrome (OMIM #615485)
Our patient was also found to have another variant – DMD C 726a>t p(Gln242His). This variant is predicted to replace the amino acid Glutamine with Histidine at position 242 in the dystrophin protein. There are no reports of this variant in any databases or in the published literature. The protein prediction algorithm within the Alamut variant analysis software package (v2.7.2) do not predict an effect on protein function and there is no evidence of an alteration to splicing. Loss of function variants in the DMD cause XP21 dystrophionopathy, however most pathogenic variants lead to a truncated protein and missense variants in DMD are usually well tolerated. Our proband has a normal creatinine kinase level and is showing no features of Xp21 dystrophionopathy therefore it is unlikely that this variant is pathogenic.
At 7 years of age he can talk in sentences, he walks independently and attends special school. He is still in nappies and there are no concerns regarding his feeding and sleeping. His height and weight are on the 91st centile and the head circumference on the 2nd centile. His facial features consist of long face, arched eyebrows, synophrys and prominent columella.
In conclusion we present a boy with milder features of BRS. He did not have the characteristic features of severe muscular hypotonia with feeding difficulties, significant speech and motor delay with epilepsy. He has mild developmental delay with some characteristic facial features with a denovo pathogenic frameshift mutation in exon 12 of ASXL3. Our case illustrates that the clinical features in BRS can show wide variation, which can present with milder features of developmental delay, facial dysmorphism and premature protein truncation.
References:
Balasubramanian M, Willoughby J, Fry AE, Weber A, Firth HV, Deshpande C, Berg JN, Chandler K, Metcalfe KA, Lam W, et al. Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature. J Med Genet. 2017 Aug; 54(8):537-543.
Hori I, Miya F, Ohashi K, Negishi Y, Hattori A, Ando N, Okamoto N, Kato M, Tsunoda T, Yamasaki M, et al Novel splicing mutation in the ASXL3 gene causing Bainbridge-Ropers syndrome. Am J Med Genet A. 2016 Jul; 170(7):1863-7.
Kuechler A, Czeschik JC, Graf E, Grasshoff U, Hüffmeier U, Busa T, Beck-Woedl S, Faivre L, Rivière JB, Bader I, et al. Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition. Eur J Hum Genet. 2017 Feb; 25(2):183-191.
Srivastava A, Ritesh KC, Tsan YC, Liao R, Su F, Cao X, Hannibal MC, Keegan CE, Chinnaiyan AM, Martin DM, Bielas SL. De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome. Hum Mol Genet. 2016 Feb 1;25(3):597-608.
We thank our colleagues for their interest in our study recently published in the Journal of Medical Genetics entitled ‘Risk assessment of maternally inherited SDHD paraganglioma and pheochromocytoma’.
In response, we would like to underline that our study is a prospective study (see 'Methods' section) and not a case study.
Today, the French national registry for hereditary paraganglioma (PGL.R) contains 193 SDHD different families carrying more than 60 different mutations, which is different from the Dutch situation where 87.1% of the SDHD-mutation carriers have the same founder Dutch mutation p.Asp92Tyr [1]. As explained in our paper, we have launched this prospective study because of the few cases of SDHD-tumors inherited via the maternal line reported in the literature, but also because we were aware of three other putative cases among patients suffering from paraganglioma or pheochromocytoma (PPGL) registered in PGL.R. Unfortunately, for those three cases we were not able to collect tumor tissues to definitely prove the role of the maternally inherited SDHD mutation in the tumorigenesis. The identification of a new case, a young asymptomatic woman, by our prospective study was nevertheless a surprise for us. So we strongly suggest our colleagues to take advantage from their large cohort of 600 at-risk subjects to perform the same prospective study in asymptomatic subjects, although most of them would carry the same SDHD founder mutation, to confi...
We thank our colleagues for their interest in our study recently published in the Journal of Medical Genetics entitled ‘Risk assessment of maternally inherited SDHD paraganglioma and pheochromocytoma’.
In response, we would like to underline that our study is a prospective study (see 'Methods' section) and not a case study.
Today, the French national registry for hereditary paraganglioma (PGL.R) contains 193 SDHD different families carrying more than 60 different mutations, which is different from the Dutch situation where 87.1% of the SDHD-mutation carriers have the same founder Dutch mutation p.Asp92Tyr [1]. As explained in our paper, we have launched this prospective study because of the few cases of SDHD-tumors inherited via the maternal line reported in the literature, but also because we were aware of three other putative cases among patients suffering from paraganglioma or pheochromocytoma (PPGL) registered in PGL.R. Unfortunately, for those three cases we were not able to collect tumor tissues to definitely prove the role of the maternally inherited SDHD mutation in the tumorigenesis. The identification of a new case, a young asymptomatic woman, by our prospective study was nevertheless a surprise for us. So we strongly suggest our colleagues to take advantage from their large cohort of 600 at-risk subjects to perform the same prospective study in asymptomatic subjects, although most of them would carry the same SDHD founder mutation, to confirm or not our data.
Based on the results of our prospective study, we suggest to inform adult patients of the potential risk and to propose them a first screening that would include imaging. Our clinical experience of 18 years of genetic counselling and management of subjects with genetically determined forms of PPGL within a specialized multidisciplinary team is different from those of our colleagues. In the PGL.EVA study [2,3], we observed a significant decrease of depression and anxiety after initial screening. In the subgroup with tumor diagnosis, we observed a tendency for decrease of depression and no increase of anxiety. In the present study, evaluation of the feeling of patients at the reception of our letter revealed their satisfaction to the interest given by an expert center and to the possibility to take advantage of science progress.
Moreover, they clearly expressed being comforted by the possibility to communicate with an expert center of the disease in case of symptoms.
We think that in 2017 a large PPGL revealed by a complication, such as deafness or cardiac complications, in SDHD mutation carrier relatives would be unacceptable. Beyond the mortality rate, which cannot be definitely assessed with a mean duration of follow-up of 7.6 years only as in the paper published by van Hulsteijn [4], the quality of life should also be considered. Interestingly, the same Dutch team reported in 2013 that the quality of life is decreased in patients with paraganglioma (significantly impaired scores on physical, psychological and social subscales) after questioning 174 patients versus 100 controls [5].
So we do believe that after several reports of clinical cases, our study is a new step forward evidencebased guidelines for SDHD families. Our current recommendations might be further re-evaluated with new data from prospective or randomized studies as well as with the assessment of the natural history of the SDHD-related disease following a prospective long term follow-up of the patients enrolled in hereditary paraganglioma registries equivalent to the French PGL.R.
Anne-Paule Gimenez-Roqueplo
Khadija Lahlou-Laforêt
Nelly Burnichon
References
[1]. Hensen EF et al. High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands. Clin Genet 2012; 81:284-288
[2]. Lahlou-Laforêt K. Consoli SM, Caumont-Prim A., Rohmer V., Gimenez-Roqueplo AP, on behalf of the PGL.EVA investigators. Psychological impact of tumor screening in SDHx mutation carriers recruited in a 3 year national protocol. IMPAHC 2015, 5-7 May 2015, Manchester
[3]. Gimenez-Roqueplo et al. Imaging Work-Up for Screening of Paraganglioma and Pheochromocytoma in SDHx Mutation Carriers: A Multicenter Prospective Study from the PGL.EVA Investigators. J Clin Endocrinol Metab 2014; 98: E162-E173
[4]. Van Hulsteijn LT et al. No evidence for increased mortality in SDHD variant carriers compared with the general population. Eur J Hum Genet 2015; :23:1713-1716
[5]. van Hulsteijn LT et al. Quality of life is decreased in patients with paragangliomas. Eur J Endocrinol 2013;168:689-97.
We are writing to comment on a recent paper published in your journal
by Burnichon and colleagues: Burnichon N, et al. Risk assessment of
maternally inherited SDHD paraganglioma and phaeochromocytoma. J Med
Genet. 2017; 54:125-133.
In this paper a case study is presented describing development of
pheochromocytoma in a carrier of an SDHD mutation. Although at first sight
not an uncommon occu...
We are writing to comment on a recent paper published in your journal
by Burnichon and colleagues: Burnichon N, et al. Risk assessment of
maternally inherited SDHD paraganglioma and phaeochromocytoma. J Med
Genet. 2017; 54:125-133.
In this paper a case study is presented describing development of
pheochromocytoma in a carrier of an SDHD mutation. Although at first sight
not an uncommon occurrence in carriers of these mutations, this case is
unusual because the mutation was inherited via the maternal line. This is
now only the third reported case of confirmed phaeochromocytoma
development following maternal transmission of an SDHD mutation. [1-3] The
patient in question was identified among a cohort of 20 maternal mutation
carriers who underwent imaging surveillance.
Based on the identification of one patient in this cohort (5%), the
authors make recommendations for the clinical care of carriers of a
maternally inherited SDHD mutation. They advise targeted familial genetic
testing from the age of 18 in families with SDHD mutations, and that
identified carriers undergo imaging and biochemical workup to detect
asymptomatic tumours. If the first workup is negative, the authors suggest
that patients be informed about paraganglioma-phaeochromocytoma (PPGL)
symptoms and recommend an annual clinical examination and blood pressure
measurement, with a new workup indicated in case of symptoms suggestive of
PPGL.
Although this paper is a meaningful contribution to the literature, we are
concerned that the authors base their subsequent clinical recommendations
on a relatively small cohort. In a recent study, we described one
confirmed case of maternal transmission and concluded that "we consider
the increase in risk represented by these reports to be negligible." [2]
Two reasons underlie this statement. Firstly, the somatic
rearrangements underlying the maternal cases identified to date are far
more complex (loss of the paternal wild-type SDHD allele by mitotic
recombination, followed by loss of the recombined paternal chromosome
containing the paternal 11q23 region and the maternal 11p15 region) than
the molecular events seen in paternal cases (loss of whole chromosome 11).
Secondly, our conclusions were based, implicitly, on many previous studies
at our centre over the past three decades in which we described various
aspects of the large SDHD cohort collected by us over that period. Genetic
aspects of this cohort, and 601 patients with paternally transmitted SDHD
mutations, were described by Hensen and co-workers in 2012. [4] As all
previous studies suggest that mutations are equally transmissible via the
paternal or maternal line, our identification of a single maternal case
among this cohort suggests that the penetrance of maternally transmitted
mutations is very low. Using the calculation employed by Burnichon and
colleagues and assuming that at least 600 maternal mutation carriers are
alive in the Netherlands, we arrive at an estimate of 0.17% (1/601 =
0.17%), rather than their figure of 5%. In addition to our own cohort,
1000's of SDHD mutation carriers have been identified world-wide. Assuming
that 1 in 20 maternally transmitted mutations result in tumours, many more
maternally inherited cases would have come to our attention, even without
surveillance.
In our opinion the question of management of maternally inherited
SDHD mutations comes down to a risk-benefit analysis. The most obvious
implication of the recommendations made by Burnichon and colleagues in our
patient population would be the institution of surveillance, with all the
attendant practical, financial and psychological burdens for 600 carriers
of maternally inherited SDHD mutations in order to identify a single case.
Furthermore, SDHD-associated PPGL mortality rates and survival in a Dutch
cohort of SDHD variant carriers was not substantially increased compared
with the general population. [5] In practice, carriers of maternally
inherited SDHD mutations at our centre are not advised to undergo
surveillance. Instead, we reassure them that their risk of developing PPGL
is exceptionally low (described three times worldwide), but that they
should be aware, more so than the general population, of symptoms that are
suggestive of paraganglioma or phaeochromocytoma. Many families have been
in our care for over 25 years and in that time we have found no evidence
to suggest that this policy should be revised.
References
1 Yeap PM, Tobias ES, Mavraki E, Fletcher A, Bradshaw N, Freel EM,
Cooke A, Murday VA, Davidson HR, Perry CG, Lindsay RS. Molecular analysis
of pheochromocytoma after maternal transmission of SDHD mutation
elucidates mechanism of parent-of-origin effect. J Clin Endocrinol Metab
2011;96:E2009-E2013.
2 Bayley JP, Oldenburg RA, Nuk J, Hoekstra AS, van der Meer CA,
Korpershoek E, McGillivray B, Corssmit EP, Dinjens WN, de Krijger RR,
Devilee P, Jansen JC, Hes FJ. Paraganglioma and pheochromocytoma upon
maternal transmission of SDHD mutations. BMC Med Genet 2014;15:111.
3 Burnichon N, Mazzella JM, Drui D, Amar L, Bertherat J, Coupier I,
Delemer B, Guilhem I, Herman P, Kerlan V, Tabarin A, Wion N, Lahlou-
Laforet K, Favier J, Gimenez-Roqueplo AP. Risk assessment of maternally
inherited SDHD paraganglioma and phaeochromocytoma. J Med Genet
2017;54:125-33.
4 Hensen EF, van DN, Jansen JC, Corssmit EP, Tops CM, Romijn JA,
Vriends AH, Van Der Mey AG, Cornelisse CJ, Devilee P, Bayley JP. High
prevalence of founder mutations of the succinate dehydrogenase genes in
the Netherlands. Clin Genet 2012;81:284-8.
5 van Hulsteijn LT, Heesterman B, Jansen JC, Bayley JP, Hes FJ,
Corssmit EP, Dekkers OM. No evidence for increased mortality in SDHD
variant carriers compared with the general population. Eur J Hum Genet
2015;23:1713-6.
Phenotypic non-penetrance in Milroy-like disease associated with a mutation in the vascular endothelial growth factor-C gene (VEGFC)
Boersma, H.J.1, M.V. Heitink2, J.M. van de Kamp3, van Geel, M 1,4
1 Department of Dermatology, Maastricht University Medical Centre+, Maastricht, The Netherlands
2 Department of Dermatology, VieCuri, Venlo, The Netherlands
3 Department of Clinical Genetics, VU Medical Centre, Amsterdam, The Netherlands
4 Department of Clinical Genetics, Maastricht University Medical Centre+, Maastricht, The Netherlands
With great interest, we read the article by Balboa-Beltran et al [1], where they presented a three-generation family with a phenotype of typical Milroy disease without mutations in FLT4 but instead in VEGFC. Milroy disease is an autosomal dominant, congenital form of primary lymphoedema with reduced penetrance. In approximately 70% of Milroy disease patients, mutations in FLT4 are identified [2]. Connell et al. presented research wherein FLT4 pathogenic variants were detected in 75% of clearly affected patients having a positive family history and in 68% of typical Milroy patients but without a family history [3], suggesting that other genes may be involved. Balboa-Beltran et al [1], detected a novel nonsense mutation (p.(Arg210*)) in VEGFC by exome sequencing causing Milroy-like disease. They found that all carriers of this VEGFC mutation exhibited the clinical diagnostic criteria of Milroy disease, inclu...
Phenotypic non-penetrance in Milroy-like disease associated with a mutation in the vascular endothelial growth factor-C gene (VEGFC)
Boersma, H.J.1, M.V. Heitink2, J.M. van de Kamp3, van Geel, M 1,4
1 Department of Dermatology, Maastricht University Medical Centre+, Maastricht, The Netherlands
2 Department of Dermatology, VieCuri, Venlo, The Netherlands
3 Department of Clinical Genetics, VU Medical Centre, Amsterdam, The Netherlands
4 Department of Clinical Genetics, Maastricht University Medical Centre+, Maastricht, The Netherlands
With great interest, we read the article by Balboa-Beltran et al [1], where they presented a three-generation family with a phenotype of typical Milroy disease without mutations in FLT4 but instead in VEGFC. Milroy disease is an autosomal dominant, congenital form of primary lymphoedema with reduced penetrance. In approximately 70% of Milroy disease patients, mutations in FLT4 are identified [2]. Connell et al. presented research wherein FLT4 pathogenic variants were detected in 75% of clearly affected patients having a positive family history and in 68% of typical Milroy patients but without a family history [3], suggesting that other genes may be involved. Balboa-Beltran et al [1], detected a novel nonsense mutation (p.(Arg210*)) in VEGFC by exome sequencing causing Milroy-like disease. They found that all carriers of this VEGFC mutation exhibited the clinical diagnostic criteria of Milroy disease, including lower-limb swelling at birth or soon thereafter and upslanting toenails. In their article, the mutation segregated with the phenotype in the family according to a dominant inheritance model with full penetrance. In an article by Gordon et al [4] it was already demonstrated that mutations in VEGFC can cause a Milroy disease-like phenotype similar to that found in patients with mutations in the FLT4 gene. We would like to add to this knowledge by presenting a new case, seen in our Dutch academic hospital.
In 2013, a young, male patient (1 year) exhibited lymphoedema in his right foot without a dilated vena saphena magna. At birth he presented with bilateral foot and lower leg lymphoedema, diminishing on the left after 3 months. The symptoms were suggestive of Milroy’s disease. To determine whether these symptoms were caused by a mutation, we performed Sanger sequence analysis for FLT4 and VEGFC and found the same heterozygous nonsense VEGFC mutation as described by Balboa-Beltran et al [1]. To determine if the mutation occurred de novo or segregated in the family, both parents were tested. The mutation was also found in his asymptomatic 28-year-old father. The patient’s paternal grandmother, also having the mutation, mentioned that she exhibited heavy peripheral oedema when she was pregnant. The paternal great-grandmother (not tested) supposedly developed extreme peripheral oedema after a uterus-extirpation in the past and we were informed that the paternal grandmother’s sister had large ankles at adult age. However, no conclusions may be drawn from the latter family members, since mutation analysis was not performed. This family suggests, in contrast to the article of Balboa-Beltran et al [1], that non-penetrance of this nonsense mutation in VEGFC is evident, in line with the patient’s initial absence of disease history within the family. Similar variable penetrance, is reported in Milroy disease associated with mutations in FLT4, where 10%-15% of individuals with an FLT4 pathogenic variant were shown to be clinically unaffected [2].
References:
1 Balboa-Beltran E, Fernandez-Seara MJ, Perez-Munuzuri A, et al. A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease. J Med Genet 2014;51(7):475-8.
2 Brice G, Child A, Evans A, et al. Milroy disease and the VEGFR-3 mutation phenotype. J Med Genet 2005;42(2):98-102.
3 Connell FC, Ostergaard P, Carver C, et al. Analysis of the coding regions of VEGFR3 and VEGFC in Milroy disease and other primary lymphoedemas. Human Genet, 2009; 124(6), 625–631.
4 Gordon K, Schulte D, Brice G, et al. Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant milroy-like primary lymphedema. Circ Res 2013;112(6):956-60.
Yuval Ramot1, Abraham Zlotogorski1, Maurice van Steensel2,3,4
1 Department of Dermatology, Hadassah - Hebrew University Medical
Center, Jerusalem, Israel
2 School of Medicine and School of Life Sciences, University of
Dundee, United Kingdom
3 Institute of Medical Biology, Singapore
4 Lee Kong Chian School of Medicine, Nanyang Technological
University, Singapore
In their recently published article, Shah et al. claim that a
homozygous loss-of-function mutation in KRT83 leads to recessive
progressive symmetric erythrokeratoderma.1 However, since KRT83 encodes a
hair-specific keratin, we believe it is highly unlikely that a mutation in
this gene would cause a strictly epidermal phenotype.
Keratins are intermediate filaments that provide structural support
to epithelial cells, in addition to other biological properties.2-4 They
are unique in that each has a very specific expression pattern, which has
been studied extensively.5 To date, mutations in hair keratins have all
been associated with phenotypes restricted to the hairs and nails.6
Specifically, mutations in KRT83 had been linked exclusively to
monilethrix.7,8
Progressive symmetric erythrokeratoderma and erythrokeratoderma
variabilis do not present with a hair phenotype. These strictly epidermal
disorders are presently grouped together as erythrokeratodermia variabilis
et progressiva (OMIM #133200) because they have the same molecular basis -
mostly autosomal dominant mutations in GJB3 and GJB4.9 The encoded
proteins are highly expressed in the epidermis.9,10
In their discussion, the authors state that keratin K83 is also
expressed outside of the hair follicle. They claim that Kb23, which is the
rat ortholog for K83, is expressed in the whole skin, but the reference
that they cite has only demonstrated expression in the hair follicle, and
not the epidermis.11 The same is true for the claimed expression in the
sheep wool follicles, where the reference cited shows expression only in
the wool follicle, and not the epidermis.12 Shah et al. also claim that
according to the human protein atlas, K83 is expressed in the skin, but
actually, it was found only in the hair and not in the epidermis
(http://www.proteinatlas.org/ENSG00000170523-KRT83/tissue). Staining as
shown in the atlas is highly restricted, even though the antibody used in
the human protein atlas is likely to recognize additional hair keratins.
The expression atlas that is also cited in the article gives information
on expression patterns of genes (http://www.ebi.ac.uk/gxa/home), and is
not based on immunohistochemistry as stated by the authors. Since the skin
samples used for expression profiling in this database are of whole skin
and not the epidermis alone, they are likely to also include parts of hair
follicles. Obviously, expression of KRT83 could be observed in these
samples. In contrast, a large number of studies demonstrate robust,
specific and reproducible expression of K83 in the hair.5,13-15 Thus, we
feel that it is safe to conclude that K83 is hair-specific and is not
expressed in human epidermis.
We consider it unlikely that mutations in a keratin that is
exclusively expressed in the hair would cause a severe epidermal phenotype
that also involves the palms and soles, areas that are devoid of hair
follicles. If they did, there would be profound implications for our
understanding of keratins, and of skin biology in general. We believe that
such a provocative claim should have been accompanied by proper
demonstration that K83 is indeed expressed in the epidermis, and
functional evidence that its loss can lead to an epidermal-specific
phenotype.
References
1 Shah K, Ansar M, Mughal ZU et al. Recessive progressive symmetric
erythrokeratoderma results from a homozygous loss-of-function mutation of
KRT83 and is allelic with dominant monilethrix. J Med Genet 2016, Dec 13,
Epub ahead of print.
2 Ramot Y, Zlotogorski A. Keratins: the hair shaft's backbone
revealed. Exp Dermatol 2015; 24: 416-7.
3 Ramot Y, Paus R. Harnessing neuroendocrine controls of keratin
expression: a new therapeutic strategy for skin diseases? Bioessays 2014;
36: 672-86.
4 Ramot Y, Paus R, Tiede S et al. Endocrine controls of keratin
expression. Bioessays 2009; 31: 389-99.
5 Moll R, Divo M, Langbein L. The human keratins: biology and
pathology. Histochem Cell Biol 2008; 129: 705-33.
6 Ramot Y, Zlotogorski A. Molecular genetics of alopecias. Curr Probl
Dermatol 2015; 47: 87-96.
7 van Steensel M, Vreeburg M, Urbina MT et al. Novel KRT83 and KRT86
mutations associated with monilethrix. Exp Dermatol 2015; 24: 222-4.
8 van Steensel MA, Steijlen PM, Bladergroen RS et al. A missense
mutation in the type II hair keratin hHb3 is associated with monilethrix.
J Med Genet 2005; 42: e19.
9 van Steensel MA, Oranje AP, van der Schroeff JG et al. The missense
mutation G12D in connexin30.3 can cause both erythrokeratodermia
variabilis of Mendes da Costa and progressive symmetric
erythrokeratodermia of Gottron. Am J Med Genet A 2009; 149A: 657-61.
10 Ishida-Yamamoto A, McGrath JA, Lam H et al. The molecular
pathology of progressive symmetric erythrokeratoderma: a frameshift
mutation in the loricrin gene and perturbations in the cornified cell
envelope. Am J Hum Genet 1997; 61: 581-9.
11 Nanashima N, Akita M, Yamada T et al. The hairless phenotype of
the Hirosaki hairless rat is due to the deletion of an 80-kb genomic DNA
containing five basic keratin genes. J Biol Chem 2008; 283: 16868-75.
12 Yu Z, Wildermoth JE, Wallace OA et al. Annotation of sheep keratin
intermediate filament genes and their patterns of expression. Exp Dermatol
2011; 20: 582-8.
13 Langbein L, Yoshida H, Praetzel-Wunder S et al. The keratins of
the human beard hair medulla: the riddle in the middle. J Invest Dermatol
2010; 130: 55-73.
14 Langbein L, Schweizer J. Keratins of the human hair follicle. Int
Rev Cytol 2005; 243: 1-78.
15 Langbein L, Rogers MA, Winter H et al. The catalog of human hair
keratins. II. Expression of the six type II members in the hair follicle
and the combined catalog of human type I and II keratins. J Biol Chem
2001; 276: 35123-32.
We only became aware of the paper by Reinstein et al. after our
manuscript was published online. It is gratifying to know that we are not
the only group who has identified left ventricular non-compaction (LVNC)
in males with loss-of-function mutations in NONO.
Matias Wagner1,2,3, Dominik S Westphal1,2, Iris Hannibal4, Johannes A. Mayr5, Tim M. Strom1,2, Thomas Meitinger1,2, Holger Prokisch1,2, Saskia B. Wortmann1,2,5
1. Institute of Human Genetics, Technical University Munich, Munich, Germany;
2. Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany;
3. Institute of Neurogenomics, Helmholtz Zentrum Munich, Neuherberg, Germany
4. Dr. von Hauner Children’s Hospital, Ludwig-Maximilians University, Munich, Germany
5. Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria
Biallelic mutations in KIAA0586 have been related to Joubert syndrome (JBTS) 23 and as the most frequent disease causing variant c.428del (p.Arg143Lysfs*4) was identified.1 However, the allele frequency of 0.003117 and two homozygotes in the gnomAD dataset as well as additional reports of healthy carriers have questioned the variant’s pathogenicity.2, 3 Pauli et al. have recently hypothesized that c.428del is a hypomorphic allele which is only causing JBTS in compound heterozygosity with other mutations.
In 15,000 in-house exome data sets, we have identified three individuals harboring c.428del in a homozygous state. In two, we identified other variants sufficiently explaining the phenotype: In a 6 year old girl with global developmental delay and progressive myoclonic astatic epilepsy, we identified a de novo variant c.2683del, p.Ser895Le...
Show MoreDear Editor,
in their recent study Arends and colleagues demonstrate a significant 2.8-fold increased risk for the formation of neutralizing anti-drug antibodies (ADA) in male patients with Fabry disease (FD) when treated with agalsidase-beta (1.0 mg/kg every other week) compared to agalsidase-alfa (0.2 mg/kg every other week).[1] Interestingly, Rombach and colleagues and later Smid and colleagues reported no significant differences in a humoral response, when using an identical dosage of 0.2 mg/kg for both drugs. [2,3] Hence, the 5-fold higher dosage of agalsidase-beta and not the compound itself seems to be an important trigger for antibody formation. However, none of the studies determined the cross reactive immunological status, which is crucial for the risk of a humoral response. The subgroup analysis of patients with ADAs by Arends and colleagues also revealed a better biochemical response to agalsidase-beta at 1.0 mg/kg in terms of decreasing lyso-Gb3 levels.[1] The authors propose that a saturation of antibody titers due to the 5-fold higher dosage might lead to the observed effect. In this respect, we recently demonstrated that antibodies can be supersaturated and that appropriate (i.e. individually optimized) enzyme dosages can overcome ADA titers already during infusions, which may result in improved patients’ outcome.[4] However, in the same study, we also demonstrated that even in patients treated with low-dose enzyme replacement therapy ADA titers can...
Show MoreWe read with interest the case series of 6 patients with Bohring-Opitz syndrome (BOS) phenotype who were found to have autosomal recessive truncating mutations in the KLHL7 gene[1]. The purpose of this letter is to report a novel truncating mutation in KLHL7, and to expand the phenotype of recessive KLHL7 variants.
Show MoreOur patient is a now 32-month-old male of Guatemalan descent who was born at 37 weeks’ gestation after a pregnancy complicated by fetal hydronephrosis, IUGR, and maternal hypertension. Birthweight was 2.5 kg, and he failed the neonatal hearing screen bilaterally. He was admitted to the NICU for desaturation events and was treated with supplemental oxygen. Polysomnography was performed at 4 weeks of life and identified central sleep apnea, with a central apnea index of 11 events/hour and no significant obstructive component. PHOX2B testing ruled out congenital central hypoventilation syndrome. A brain MRI demonstrated hypoplasia of the corpus callosum, delayed myelination, pontine hypoplasia, and subependymal nodular heterotopia along the lateral ventricles. A chromosome microarray was negative for deletions and duplications, though it indicated multiple areas of homozygosity (combined total length ~24 Mb).
He demonstrated some neck control at 3 months of age, and at age 2 years was able to roll for mobility. He remains nonverbal, tracheosteomy- and gastrostomy tube-dependent. Kyphoscoliosis was noted at 11 months of age and is progressing. He is also...
We read with interest the case series of 12 patients with loss-of-function denovo heterozygous mutations in ASXL3, reported by Balasubramanian et al in August 2017. We want to report on a further case of Bainbridge – Ropers Syndrome (BRS) seen in our department. The purpose of this letter is two-fold. The first is to report on the mild features of BRS and the second is to expand the spectrum of features in BRS reiterating that all cases may not have severe features.
The proband is now 7 years old who first presented to the genetic services at the age of 3 years with global developmental delay and epilepsy. He is the first child of non-consanguineous healthy parent of Indian heritage. There is no family history of learning difficulties, autism or developmental delay.
He was born after a normal pregnancy by LSCS for prolonged labour with a birth weight of 2.9kg at term. He started sitting independently at 16 months and walking at 22 months. He has speech and language delay. He initially presented with 2 episodes of febrile convulsions; the first lasting 1 minute and second 10 minutes, at 3 and a half years of age. He then went on to develop tonic- clonic seizures thereafter all requiring hospital admission. He was recruited to the deciphering development disorder project (DDD) and on whole exome sequencing detected two variants in ASXL3 and DMD gene respectively.
This variant is predicted to cause a frameshift mutation resulting in a premature terminat...
Show MoreWe thank our colleagues for their interest in our study recently published in the Journal of Medical Genetics entitled ‘Risk assessment of maternally inherited SDHD paraganglioma and pheochromocytoma’.
Show MoreIn response, we would like to underline that our study is a prospective study (see 'Methods' section) and not a case study.
Today, the French national registry for hereditary paraganglioma (PGL.R) contains 193 SDHD different families carrying more than 60 different mutations, which is different from the Dutch situation where 87.1% of the SDHD-mutation carriers have the same founder Dutch mutation p.Asp92Tyr [1]. As explained in our paper, we have launched this prospective study because of the few cases of SDHD-tumors inherited via the maternal line reported in the literature, but also because we were aware of three other putative cases among patients suffering from paraganglioma or pheochromocytoma (PPGL) registered in PGL.R. Unfortunately, for those three cases we were not able to collect tumor tissues to definitely prove the role of the maternally inherited SDHD mutation in the tumorigenesis. The identification of a new case, a young asymptomatic woman, by our prospective study was nevertheless a surprise for us. So we strongly suggest our colleagues to take advantage from their large cohort of 600 at-risk subjects to perform the same prospective study in asymptomatic subjects, although most of them would carry the same SDHD founder mutation, to confi...
Dear Editor,
We are writing to comment on a recent paper published in your journal by Burnichon and colleagues: Burnichon N, et al. Risk assessment of maternally inherited SDHD paraganglioma and phaeochromocytoma. J Med Genet. 2017; 54:125-133.
In this paper a case study is presented describing development of pheochromocytoma in a carrier of an SDHD mutation. Although at first sight not an uncommon occu...
Phenotypic non-penetrance in Milroy-like disease associated with a mutation in the vascular endothelial growth factor-C gene (VEGFC)
Boersma, H.J.1, M.V. Heitink2, J.M. van de Kamp3, van Geel, M 1,4
1 Department of Dermatology, Maastricht University Medical Centre+, Maastricht, The Netherlands
2 Department of Dermatology, VieCuri, Venlo, The Netherlands
3 Department of Clinical Genetics, VU Medical Centre, Amsterdam, The Netherlands
4 Department of Clinical Genetics, Maastricht University Medical Centre+, Maastricht, The Netherlands
With great interest, we read the article by Balboa-Beltran et al [1], where they presented a three-generation family with a phenotype of typical Milroy disease without mutations in FLT4 but instead in VEGFC. Milroy disease is an autosomal dominant, congenital form of primary lymphoedema with reduced penetrance. In approximately 70% of Milroy disease patients, mutations in FLT4 are identified [2]. Connell et al. presented research wherein FLT4 pathogenic variants were detected in 75% of clearly affected patients having a positive family history and in 68% of typical Milroy patients but without a family history [3], suggesting that other genes may be involved. Balboa-Beltran et al [1], detected a novel nonsense mutation (p.(Arg210*)) in VEGFC by exome sequencing causing Milroy-like disease. They found that all carriers of this VEGFC mutation exhibited the clinical diagnostic criteria of Milroy disease, inclu...
Show MoreYuval Ramot1, Abraham Zlotogorski1, Maurice van Steensel2,3,4
1 Department of Dermatology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel
2 School of Medicine and School of Life Sciences, University of Dundee, United Kingdom
3 Institute of Medical Biology, Singapore
4 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
In their rec...
We only became aware of the paper by Reinstein et al. after our manuscript was published online. It is gratifying to know that we are not the only group who has identified left ventricular non-compaction (LVNC) in males with loss-of-function mutations in NONO.
Conflict of Interest:
None declared
The association has been described before but is not cited in the JMG manuscript
Eur J Hum Genet. 2016 Jun 22. doi: 10.1038/ejhg.2016.72.
Intellectual disability and non-compaction cardiomyopathy with a de novo NONO mutation identified by exome sequencing.
Conflict of Interest:
None declared
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