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.
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.
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.
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.
Enabled by recent advances in sequencing technologies, genotypes from thousands of individuals are now available in online databases. While most of them aim to be the reference source of genotypes from healthy individuals, however, due to the lack of accompanying clinical data, geneticists now face the challenge of separating pathogenic mutations and rare polymorphisms. The fr...
Enabled by recent advances in sequencing technologies, genotypes from thousands of individuals are now available in online databases. While most of them aim to be the reference source of genotypes from healthy individuals, however, due to the lack of accompanying clinical data, geneticists now face the challenge of separating pathogenic mutations and rare polymorphisms. The frequency of pathogenic variants within a population database could be inflated by subjects who are not yet diagnosed or misdiagnosed. In particular, it is more challenging for geneticists working on late on-set neurodegenerative diseases, such as SCA40 (1), where pathogenic variants may lurk within the genome for decades, until gradual deterioration of symptoms could be observed. In the case of SCA34, only 63% of ELOVL4 L168F carriers demonstrated ataxia (2). This is possibly due to the relatively young age of carriers (less than 48 years old), and thus the ataxia symptoms take time to develop (2).
The ExAC database (3) is one of the largest genotype databases to date, which combines sequencing data from 60,706 unrelated individuals in cohorts such as National Institute of Mental Health Controls, schizophrenia, bipolar disorder, Tourette's syndrome, and The Cancer Genome Atlas (TCGA). This clearly shows that pathogenic variants can be found in ExAC, and thus it might not be suitable to be treated as the genetic background of healthy population. MacArthur et. al. (3) have clearly stated that ExAC was designed to be the reference data set for childhood-onset Mendelian diseases, and the subjects are free of known severe pediatric diseases only[1]. Therefore, it is questionable to claim a variant as rare polymorphism based on ExAC alone.
To illustrate the prevalence of neurodegenerative diseases markers in population genetics databases, we have screened all known markers of autosomal dominant Spinocerebellar Ataxia (SCA) and Spastic Paraplegia (SPG) other than SCA40 (Table 1). Altogether, 12 SCA markers and 6 SPG markers were found in the analysis with allele frequency ranging from 8.236e-06 to 0.0262. This reaffirms the notion that subjects with neurodegenerative diseases may exist in population genetics databases. It is known that the pathogenicity of a disease marker can change in different ethnicity background (4, 5). Ethnic specific modifiers may alter the penetrance of these markers, accounting for higher frequency of these markers in certain populations (5, 6). Since SCA40 marker induces apoptosis through JNK pathway activation (1), the relative activity of JNK1/2/3 and c-Jun could modulate the levels of apoptosis (7-9), regulating the penetrance of SCA40 marker as a result.
Besides, we believe the eLetter authors misinterpreted 1000 genome phase III frequency for CCDC88C R464H, since only R464C and R464S (rs371123543) could be found in the data according to NCBI 1000 Genome browser (Figure 1). To date, CCDC88C R464H is still unreported in 1000 Genomes phase III, 1KJPN (10), ESP6500, GoNL (11), SGVP (12), and UK10K ALSPAC/TWINSUK cohort (13). The absence of CCDC88C R464H in 1KJPN database, which curates the whole-genome sequences of 1,070 healthy Japanese individuals, clearly contradicts with the eLetter authors' claim that the variant is relatively common in Japanese control alleles. In our original study, we screened 199 local healthy subjects, but none of them harbours R464H. The eLetter authors also independently screened 24 local healthy subjects and 85 disease controls, yet the variant was only found in one patient with SOD1-associated autosomal dominant amyotrophic lateral sclerosis (ALS). Given the extremely low frequency of CCDC88C R464H variant in the population, it is unlikely that R464H represents a rare polymorphism. Of note, cerebellar ataxia was previously reported in an ALS case associated with SOD1 variants (14), so the cerebellar features of the patient containing both SOD1 and CCDC88C R464H variants merits further investigation.
To explore the possibility of finding additional disease markers in our patient samples after the publication of our study in 2014, we now reanalyzed the sequencing data using the latest human genome reference (GRCh38), updated BWA alignment tool (version 0.7.15) (15), GATK haplotypecaller variant caller (Version 3.5) (16), Clinvar database (build 20160831), dbSNP 147, and 1000 genome database phase 3, yet no other known pathogenic marker was further identified. In addition to our in-house variant prioritization method as outlined in our original study, we did not observe any discrepancy after cross-checking our results against KGGSeq results (17). Together with the support of multipoint parametric genetic linkage analysis, gene expression profile mining and functional impact predictions as described in our study, we believe we have gathered substantial in silico evidence to support CCDC88C R464H as a disease marker.
In addition to the in silico predictions that the CCDC88C R464H is a pathogenic mutation, here we provide additional functional evidence that the CCDC88C R464H activated the JNK-caspase pathway in the primary neuronal cells derived from the mammalian brain. We used the day-18 rat embryonic cortical neurons as our experimental cell model. Similar to the results we previously obtained from the human HEK293 cells, overexpression of the CCDC88C R464H induced the JNK hyperphosphorylation and caspase-3 cleavage in rat primary cortical neurons (Figure 2). This result therefore strengthened our hypothesis that CCDC88C R464H triggers apoptosis and contributes to the cerebellar atrophy in SCA40 patients.
Table 1--Screening of autosomal dominant Spinocerebellar ataxia and Spastic paraplegia markers in population genetics databases.
Figure 1--CCDC88C variants around Arg-464 position in 1000 Genome Phase III.
Figure 2--Overexpression of the CCDC88C R464H DNA construct induced JNK hyperphosphorylation and caspase-3 cleavage in rat primary cortical neuronal cells. Two independent trials (Set1 and Set2) were performed and the results are consistent.
References
1. Tsoi,H., Yu,A.C.S., Chen,Z.S., Ng,N.K.N., Chan,A.Y.Y., Yuen,L.Y.P., Abrigo,J.M., Tsang,S.Y., Tsui,S.K.W., Tong,T.M.F., et al. (2014) A novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia. J. Med. Genet., 51, 590-5.
2. Cadieux-Dion,M., Turcotte-Gauthier,M., Noreau,A., Martin,C., Meloche,C., Gravel,M., Drouin,C.A., Rouleau,G.A., Nguyen,D.K. and Cossette,P. (2014) Expanding the clinical phenotype associated with ELOVL4 mutation: study of a large French-Canadian family with autosomal dominant spinocerebellar ataxia and erythrokeratodermia. JAMA Neurol., 71, 470-5.
3. Lek,M., Karczewski,K.J., Minikel,E. V., Samocha,K.E., Banks,E., Fennell,T., O'Donnell-Luria,A.H., Ware,J.S., Hill,A.J., Cummings,B.B., et al. (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature, 536, 285-291.
4. Pollak,A., Skorka,A., Mueller-Malesi?ska,M., Kostrzewa,G., Kisiel,B., Waligora,J., Krajewski,P., O?dak,M., Korniszewski,L., Skarzy?ski,H., et al. (2007) M34T and V37I mutations in GJB2 associated hearing impairment: evidence for pathogenicity and reduced penetrance. Am. J. Med. Genet. A, 143A, 2534-43.
5. Mannan,A.U. (2008) Response to Martignoni et al. Am. J. Hum. Genet., 83, 128-130.
6. Smeets,C.J.L.M. and Verbeek,D.S. (2016) Reply: SCA23 and prodynorphin: is it time for gene retraction? Brain, 139, e43.
7. Ham,J., Babij,C., Whitfield,J., Pfarr,C.M., Lallemand,D., Yaniv,M. and Rubin,L.L. (1995) A c-Jun dominant negative mutant protects sympathetic neurons against programmed cell death. Neuron, 14, 927-39.
8. Yang,D.D., Kuan,C.Y., Whitmarsh,A.J., Rincon,M., Zheng,T.S., Davis,R.J., Rakic,P. and Flavell,R.A. (1997) Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. Nature, 389, 865-70.
9. Kuan,C.Y., Yang,D.D., Samanta Roy,D.R., Davis,R.J., Rakic,P. and Flavell,R.A. (1999) The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron, 22, 667-76.
10. Nagasaki,M., Yasuda,J., Katsuoka,F., Nariai,N., Kojima,K., Kawai,Y., Yamaguchi-Kabata,Y., Yokozawa,J., Danjoh,I., Saito,S., et al. (2015) Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals. Nat. Commun., 6, 8018.
11. Francioli,L.C., Menelaou,A., Pulit,S.L., van Dijk,F., Palamara,P.F., Elbers,C.C., Neerincx,P.B.T., Ye,K., Guryev,V., Kloosterman,W.P., et al. (2014) Whole-genome sequence variation, population structure and demographic history of the Dutch population. Nat. Genet., 46, 818-825.
12. Teo,Y.-Y., Sim,X., Ong,R.T.H., Tan,A.K.S., Chen,J., Tantoso,E., Small,K.S., Ku,C.-S., Lee,E.J.D., Seielstad,M., et al. (2009) Singapore Genome Variation Project: a haplotype map of three Southeast Asian populations. Genome Res., 19, 2154-62.
13. Walter,K., Min,J.L., Huang,J., Crooks,L., Memari,Y., McCarthy,S., Perry,J.R.B., Xu,C., Futema,M., Lawson,D., et al. (2015) The UK10K project identifies rare variants in health and disease. Nature, 526, 82-90.
14. Yasser,S., Fecto,F., Siddique,T., Sheikh,K.A. and Athar,P. (2010) An unusual case of familial ALS and cerebellar ataxia. Amyotroph. Lateral Scler., 11, 568-70.
15. Li,H. and Durbin,R. (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics, 25, 1754-60.
16. McKenna,A., Hanna,M., Banks,E., Sivachenko,A., Cibulskis,K., Kernytsky,A., Garimella,K., Altshuler,D., Gabriel,S., Daly,M., et al. (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res., 20, 1297-303.
17. Li,M.-X., Gui,H.-S., Kwan,J.S.H., Bao,S.-Y. and Sham,P.C. (2012) A comprehensive framework for prioritizing variants in exome sequencing studies of Mendelian diseases. Nucleic Acids Res., 40, e53.
The report that a novel missense mutation in CCDC88C activates the
JNK pathway and causes a dominant form of spinocerebellar ataxia that
appeared in your Journal (1) is of great interest. Although we identified
the same heterozygous missense variation (c.1391G>A, p.R464H) as that
reported (1) in a Japanese patient with autosomal dominant cerebellar
ataxia (ADCA), we report here that this varia...
The report that a novel missense mutation in CCDC88C activates the
JNK pathway and causes a dominant form of spinocerebellar ataxia that
appeared in your Journal (1) is of great interest. Although we identified
the same heterozygous missense variation (c.1391G>A, p.R464H) as that
reported (1) in a Japanese patient with autosomal dominant cerebellar
ataxia (ADCA), we report here that this variation in the CCDC88C gene may
not cause ADCA.
The proband in our family is a 55-year-old female. She visited our
hospital because of unsteadiness of gait at age 49. Neurological
examination revealed mild limb and truncal cerebellar ataxia. Brain MRI
revealed cerebellar atrophy. Molecular analysis of the patient excluded
SCA1, SCA2, MJD, SCA6, SCA7, SCA8, SCA12, SCA17, SCA31, SCA36 and DRPLA.
We have followed her as an outpatient and the symptoms have progressed
mildly over the past six years.
The father noted unsteadiness of gait at age 50. His cerebellar
ataxia progressed and he died due to aspiration pneumonia at age 87. The
mother at age 85 and two sisters at ages 57 and 53 showed no neurological
deficits. Unfortunately, we could not get information on the father's
grandparents.
On whole exome sequencing, we identified a heterozygous variation
(c.1391G>A , p.R464H) in the CCDC88C gene as the most likely candidate
causative mutation because this location is highly conserved among species
(1), and bioinformatic analyses including Mutation Taster, PROVEN, and
SIFT predicted it to be disease-causing (1). Then we continued to examine
whether or not this mutation cosegregates with the disease in our
pedigree. Unexpectedly, both affected and unaffected individuals in our
family exhibited the same heterozygous variation on Sanger sequencing.
Moreover, there is a relatively high rate of this variation among Japanese
control alleles, and ExAC revealed 21 A alleles in a total of 119,910
chromosomes. In addition, the minor allele counts in 1,000 genomes and
HGVD were 0.05% and 0.3%, respectively. We checked whether or not
c.1391G>A could be a common variant in the local population in 24 local
healthy subjects and 85 disease controls. Although the variant was not
found in the former, it was found in a 48-year-old patient with a SOD1
mutation with autosomal dominant amyotrophic lateral sclerosis in the
latter. Thus, this heterozygous variation (c. 1391G>A, p.464H) in the
CCDC88C gene may not cause ADCA.
This study was approved by the institutional review board of
Yamanashi University, and informed consent was obtained from all
participating individuals.
Reference
1. Tsoi H, Yu AC, Chen ZS, Ng NK, Chan AY, Yuen LY, Abrigo JM, Tsang
SY, Tsui SK, Tong TM, Lo IF, Lam ST, Mok VC, Wong LK, Ngo JC, Lau KF, Chan
TF, Chan HY. A novel missense mutation in CCDC88C activates the JNK
pathway and causes a dominant form of spinocerebellar ataxia. J Med Genet
2014; 51: 590-595.
Response to e letter ID jmedgenet el; 2826 by Refaeli et al., dated
June14, 2016
A considerable amount of literature on the role of podocalyxin-like
(PODXL) protein in normal mammalian kidney functions and to a lesser
extent in mouse brain development is available. We agree that these
studies particularly, "Anuria, Omphalocele, and Perinatal Lethality in
Mice Lacking the Cd34-Related Protein Podocalyxin" by Doyonnas et...
Response to e letter ID jmedgenet el; 2826 by Refaeli et al., dated
June14, 2016
A considerable amount of literature on the role of podocalyxin-like
(PODXL) protein in normal mammalian kidney functions and to a lesser
extent in mouse brain development is available. We agree that these
studies particularly, "Anuria, Omphalocele, and Perinatal Lethality in
Mice Lacking the Cd34-Related Protein Podocalyxin" by Doyonnas et al (1)
and "Podocalyxin is a Novel Polysialylated Neural Adhesion Protein with
Multiple Roles in Neural Development and Synapse Formation" by Vitureira
et al (2) using podxl -/- mouse embryos and newborns have unequivocally
demonstrated the role of this gene in renal function and brain development
respectively. Doyonnas et al., (1) in their paper do mention that i)
anuria and renal failure is evidenced only postnatally as there is
possible maternal clearance in the embryos; ii) there is no evidence of
extensive proteinuria, which is characteristic of leaky podocyte
filtration in human nephrotic syndromes; and iii) more importantly, that
there were no developmental anomalies in the hematopoietic and vascular
endothelial cells which also express high levels of podocalyxin. The last
observation, authors hypothesized, may have been enabled through
functional compensation by other sialomucins such as CD34. Data on the
status of neural development in their newborn mice with identical genetic
background, which would have proved the effect of podxl deficiency in
these two vital processes is however missing in their paper. Overall, the
results from these mouse studies suggest that i) podxl protein is almost
ubiquitous in expression, multifunctional, may have varying interacting
partners and that functional/genetic redundancy exists.
In our opinion, these features of PODXL are exactly what the two mutation
studies in this gene one on autosomal dominant familial focal and
segmental glomerulosclerosis (FSGS) (3) and our study on autosomal
recessive juvenile parkinsonism (4) reflect. This is not unexpected
considering the different genetic backgrounds in different families.
Notably, in the paper by Barua et al, (3) i) the incomplete penetrance of
the private variant p.L442R (i.e., one individual carrying the mutation
but asymptomatic even at 53 years of age); ii) varying age of onset
ranging from early teenage to adulthood but developing end stage renal
disease between 2nd to 6th decade of life; iii) varying disease severity
across affected individuals in the family but certainly not post-
natal/newborn mortality (unlike in mice); and iv) rarity of mutations in
PODXL gene in 176 additional FSGS families; together with mutant PODXL
protein characterization in vitro which showed that the index mutation
results in dimerization but does not alter protein stability,
extracellular domain glycosylation, cell surface expression, global
subcellular localisation and interactions with its intracellular binding
partner ezrin are all the features of PODXL gene that need to be kept in
mind prior to assigning it an indispensable role in kidney function and
survival in humans. It is indeed appropriate that Barua et al (3) conclude
that rare variants with low statistical genetic evidence such as observed
in their study do not contribute significantly to glomerular disease in
humans.
Based on these observations, it is not unlikely that the index family
with ARJP with homozygous mutations predicted to result in loss of protein
did not manifest any symptoms of FSGS or any other kidney dysfunction,
based on the data of last clinical examination in 2009. As for the two
other concerns of Refaeli et al on the index mutation being unlikely of
germline origin and NGS errors, both can be disregarded as both the
parents are heterozygous for the index mutation (data not shown), and all
informative NGS data are validated by Sanger sequencing. Further, their
concern that mutations identified in unrelated PD cohort are just common
protein altering variants is also ruled out as these were not observed in
either our population or reported in any publically available large
databases and therefore, were functionally characterized in our study. As
for the demonstration of absence of PODXL RNA or protein, we have not been
able to do that due to non-availability of tissues. It may please be noted
that in the absence of clinical indications, it is difficult to obtain
ethical committee clearance for collection of target tissues.
In summary, from careful interpretation of the findings in the above
mentioned studies as well as abundant data in literature [for eg. See Liao
and Zhang, PNAS, 2008 (5)], it is clear that there are notable
differences between mice and humans in i) the developmental phenomena; ii)
functional compensatory mechanisms/genetic redundancy; iii) gene-gene
interactions; iv) tissue specific transcript expression etc. Though
experimental evidence for most of these aspects with specific reference to
PODXL is currently unavailable, such differences may be believed to be
useful to explain pleiotropy in PODXL [for eg. similar to that documented
in cystic fibrosis (6)], possible tolerance to null alleles enabling
apparently normal kidney function as witnessed in the ARJP family in our
study (4) and comparatively late age of onset of FSGS, incomplete
penetrance of the gene mutation etc. (3) and several other associated
features.
Finally, we would like to thank Rafaeli et al for their interest in our
work and giving us an opportunity to highlight some of the differences
which may exist between humans and mice in general and for role of
podocalyxin in particular. We firmly believe that findings from animal
models of human diseases are powerful tools but are not always true
representatives for understanding complete human health and disease
biology. Additional data as and when available on PODXL associated human
phenotypes would be most insightful for our enhanced understanding of the
role of PODXL in humans.
References:
1. Doyonnas R, Kershaw DB, Duhme C, et al. Anuria, omphalocele, and
perinatal lethality in mice lacking the CD34-related protein podocalyxin.
J Exp Med 2001;194(1):13-27.
2. Vitureira N, Andres R, Perez-Martinez E, et al. Podocalyxin is a novel
polysialylated neural adhesion protein with multiple roles in neural
development and synapse formation. PLoS One 2010;5(8):e12003.?
3. Barua M, Shieh E, Schlondorff J, et al. Exome sequencing and in vitro
studies identified podocalyxin as a candidate gene for focal and segmental
glomerulosclerosis. Kidney Int 2014;85(1):124-33.
4. Sudhaman S, Prasad K, Behari M, et al. Discovery of a frameshift
mutation in podocalyxin-like (PODXL) gene, coding for a neural adhesion
molecule, as causal for autosomal-recessive juvenile Parkinsonism. J Med
Genet 2016; 53(7):450-6.
5. Liao B, Zhang J. Null mutations in human and mouse orthologs frequently
result in different phenotypes. PNAS 2008;105(19):6987-92.
6. Sing C, Risser D, Howatt W, Erickson R. Phenotypic heterogeneity in
cystic fibrosis. American Journal of Medical Genetics 1982;13:179-195.
Conflict of Interest:
None declared
Dr. Sumedha Sudhaman1 Prof. Kameshwar Prasad2 Prof. Madhuri Behari2
Dr. Uday B Muthane3 Dr. Ramesh C Juyal4 Prof. BK Thelma1 1Department of
Genetics, University of Delhi South Campus, New Delhi, India 2Department
of Neurology, All India Institute of Medical Sciences, New Delhi, India
3Parkinson's and Ageing Research Foundation, Bengaluru, Karnataka, India
4Regional Center for Biotechnology, Faridabad, Haryana, India
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 MorePhenotypic 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 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...
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 rec...
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
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
To the Editor of Journal of Medical Genetics:
Enabled by recent advances in sequencing technologies, genotypes from thousands of individuals are now available in online databases. While most of them aim to be the reference source of genotypes from healthy individuals, however, due to the lack of accompanying clinical data, geneticists now face the challenge of separating pathogenic mutations and rare polymorphisms. The fr...
To the editor:
The report that a novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia that appeared in your Journal (1) is of great interest. Although we identified the same heterozygous missense variation (c.1391G>A, p.R464H) as that reported (1) in a Japanese patient with autosomal dominant cerebellar ataxia (ADCA), we report here that this varia...
Response to e letter ID jmedgenet el; 2826 by Refaeli et al., dated June14, 2016 A considerable amount of literature on the role of podocalyxin-like (PODXL) protein in normal mammalian kidney functions and to a lesser extent in mouse brain development is available. We agree that these studies particularly, "Anuria, Omphalocele, and Perinatal Lethality in Mice Lacking the Cd34-Related Protein Podocalyxin" by Doyonnas et...
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