Clin Genet 2015: 88: 300–302 Printed in Singapore. All rights reserved
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12544
Letter to the Editor
Expanding the phenotype of a recurrent de novo variant in PACS1 causing intellectual disability To the Editor: Intellectual disabilities (ID), like other neurodevelopmental disorders, are characterized by substantial genetic heterogeneity and clinical variability. Finding the correct genetic diagnosis poses a major challenge even for experienced clinical geneticists. The implementation of genome–wide technologies such as microarray analysis and whole exome sequencing (WES) has dramatically increased the diagnostic yield (1). We applied proband-parents WES in a boy with unexplained ID. The patient is a 3-year-old boy with moderate developmental delay, congenital heart defect, chronic constipation and low levels of immunoglobulins. His medical history and clinical features are detailed in Table 1 and in the Appendix S1, Supporting Information. Previously, conventional chromosomal analysis, microarray analysis and sequence analysis of PTPN11, KRAS, SOS1 and RAF1 had not revealed any disease causing variants. Trio exome analysis revealed a heterozygous de novo missense mutation in exon 4 of PACS1 (c.[607C>T];[=], p.[Arg203Trp];[=], according to NM_018026.3). The variant was confirmed by Sanger sequencing. For detailed information on the methods applied see Appendix S1. The same variant in PACS1 has already been detected in two individuals by Schuurs-Hoeijmakers et al. (2). The authors had adopted proband-parents WES in two individuals with remarkably similar facial dysmorphisms in a cohort of >5000 individuals with ID. Characterization of the two patients lead to the delineation of a novel distinct ID syndrome designated MRD17 (mental retardation autosomal dominant 17, MIM#615009). The two patients reported previously and the one of this report – all males from European descent – share a similar but rather unspecific clinical history (Table 1). They were born with normal birth measurements and their weight and height lies within normal limits, whereas the head circumference is relatively small but still above the third centile. All have moderate ID and a pleasant personality. Organ malformations include urogenital anomalies (2/3), malformation of the cerebellum (1/2), scoliosis (1/3) and heart defects (1/3). One of the patients described in the publication of Schuurs-Hoeijmakers et al. was tested for Cornelia de Lange syndrome, while
300
the combination of feeding difficulties with the facial features and the heart defect prompted us to test our patient for a rasopathy. At the level of the appearance of the three patients, they have strikingly similar and distinctive facial features, which are characterized by the combination of down-slanting palpebral fissures, hypertelorism, a wide mouth with down-turned corners and thin upper lips in the shape of a cupid’s bow (Fig. 1a). Additional overlapping features include large and low-set ears, a bulbous tip of the nose and curly hair. PACS1 is a trans-golgi-membrane traffic regulator that directs protein cargo (3). It is highly expressed in brain during embryonic development and is down regulated in the postnatal period (4). The recurrent variant c.[607C>T];[=], p.[Arg203Trp];[=] is located in close proximity to the CK2-binding motif and therefore possibly influences the binding properties of PACS1 (Fig. 1b). Antisense experiments in zebrafish led to the suggestion that this variant exerts a dominant negative effect by influencing the fate of SOX10-positive neural crest cells, thus creating the facial dysmorphisms (2). However, additional patients and more detailed functional experiments are needed to confirm this hypothesis and establish a genotype–phenotype correlation. Interestingly, despite the application of WES in large cohorts of patients with neurodevelopmental disorders such as ID, autism and epilepsy, neither variants in PACS1 nor in its close family member, PACS2, have been reported in the literature so far. Moreover, microdeletions encompassing PACS1 on 11q13.1 seem to be very rare events. The DECIPHER database lists only one individual carrying a heterozygous deletion of about 1.1 Mb encompassing PACS1 (https://decipher.sanger.ac.uk). The deletion covers additional 45 RefSeq genes, and the patient seems to display a complex pattern of malformations and dysmorphisms characteristic for a contiguous microdeletion syndrome. This individual, therefore, does not add to delineate the phenotype caused by haploinsufficiency of PACS1. In summary, the recurrent variant c.[607C>T];[=], p.[Arg203Trp];[=] in PACS1 causes the ID syndrome MRD17. Here, we report the third patient with MRD17, providing additional evidence that this variant causes a
Letter to the Editor
Table 1. Clinical features of patients carrying a recurrent PACS1 variant
Age at last examination Pregnancy/delivery Neonatal period
Measurements Weight Length Head circumference Urogenital features
Cerebral MRI
Development Free walking First words IQ Behavior Additional findings
Patient 1 (male); Schuurs-Hoeijmakers et al. (2)
Patient 2 (male); Schuurs-Hoeijmakers et al. (2)
Patient from the present report (male)
3 years 6 m Vacuum extraction at term Seizures Intestinal malrotation Resection of the small intestine, short bowel syndrome
19 years C-section at term No problems recorded
3 years C-section at term Hypotonia Poor weight gain Low IgG levels
15 kg (16th centile) 102 cm (50th centile) 49 cm (16th centile) Cryptorchidism Vesico-urethral reflux Streak testis Cavum septum pellucidum
64.5 kg (16th centile) 181 cm (50th centile) 55.1 cm (16th centile) Unilateral cryptorchidism Unilateral hypoplastic scrotum
13.3 kg (10–25th centile) 95 cm (25th centile) 48.5 cm (10th centile) Normal genitalia
Partial agenesis of the vermis Hypoplasia of the cerebellar hemispheres
Not done
2 years 6 m Not reported 53 Friendly, outgoing
2 years 10 m 3 years No formal assessment Friendly
Mild scoliosis Multiple pigmented nevi
Patent ductus arteriosus Atrial septal defect Small ventricular septal defect Chronic constipation
3 years 4 m 3 years 6 m T];[=], p.[Arg203Trp];[=]) is adjacent to the CK2 binding motif (RRKRY200 ).
301
Letter to the Editor c CeGaT
highly recognizable facial phenotype and broadening the phenotypic spectrum of MRD17.
GmbH Tübingen, Germany, and d MVZ genteQ Hamburg, Germany
Supporting Information Additional supporting information may be found in the online version of this article at the publisher’s web-site.
† These
authors contributed equally to this work.
Acknowledgements
References
The authors would like to thank the parents of the boy for supporting this publication. This study makes use of data generated by the DECIPHER Consortium. A complete list of centres that contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from [email protected]. Funding for the project was provided by the Wellcome Trust.
1. Willemsen MH, Kleefstra T. Making headway with genetic diagnostics of intellectual disabilities. Clin Genet 2014: 85: 101–110. 2. Schuurs-Hoeijmakers JH, Oh EC, Vissers LE et al. Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome. Am J Hum Genet 2012: 91: 1122–1127. 3. Youker RT, Shinde U, Day R, Thomas G. At the crossroads of homoeostasis and disease: roles of the PACS proteins in membrane traffic and apoptosis. Biochem J 2009: 421: 1–15. 4. Wan L, Molloy SS, Thomas L et al. PACS-1 defines a novel gene family of cytosolic sorting proteins required for trans-Golgi network localization. Cell 1998: 94: 205–216.
D. Gadzickia,† D. Döckerb,† M. Schubachc M. Menzelc B. Schmorla F. Stellmerd S. Biskupb,c,† D. Bartholdib,† a MVZ Endokrinologikum Hannover Hannover, Germany b Institute of Clinical Genetics Klinikum Stuttgart Stuttgart, Germany
302
Correspondence: Deborah Bartholdi, MD Institute of Clinical Genetics Klinikum Stuttgart Kriegsbergstr. 60-62 D-70174 Stuttgart Germany Tel.: +49 (0)711 278 74001; Fax: +49 (0)711 278 74000; e-mail: [email protected]
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12544
Letter to the Editor
Expanding the phenotype of a recurrent de novo variant in PACS1 causing intellectual disability To the Editor: Intellectual disabilities (ID), like other neurodevelopmental disorders, are characterized by substantial genetic heterogeneity and clinical variability. Finding the correct genetic diagnosis poses a major challenge even for experienced clinical geneticists. The implementation of genome–wide technologies such as microarray analysis and whole exome sequencing (WES) has dramatically increased the diagnostic yield (1). We applied proband-parents WES in a boy with unexplained ID. The patient is a 3-year-old boy with moderate developmental delay, congenital heart defect, chronic constipation and low levels of immunoglobulins. His medical history and clinical features are detailed in Table 1 and in the Appendix S1, Supporting Information. Previously, conventional chromosomal analysis, microarray analysis and sequence analysis of PTPN11, KRAS, SOS1 and RAF1 had not revealed any disease causing variants. Trio exome analysis revealed a heterozygous de novo missense mutation in exon 4 of PACS1 (c.[607C>T];[=], p.[Arg203Trp];[=], according to NM_018026.3). The variant was confirmed by Sanger sequencing. For detailed information on the methods applied see Appendix S1. The same variant in PACS1 has already been detected in two individuals by Schuurs-Hoeijmakers et al. (2). The authors had adopted proband-parents WES in two individuals with remarkably similar facial dysmorphisms in a cohort of >5000 individuals with ID. Characterization of the two patients lead to the delineation of a novel distinct ID syndrome designated MRD17 (mental retardation autosomal dominant 17, MIM#615009). The two patients reported previously and the one of this report – all males from European descent – share a similar but rather unspecific clinical history (Table 1). They were born with normal birth measurements and their weight and height lies within normal limits, whereas the head circumference is relatively small but still above the third centile. All have moderate ID and a pleasant personality. Organ malformations include urogenital anomalies (2/3), malformation of the cerebellum (1/2), scoliosis (1/3) and heart defects (1/3). One of the patients described in the publication of Schuurs-Hoeijmakers et al. was tested for Cornelia de Lange syndrome, while
300
the combination of feeding difficulties with the facial features and the heart defect prompted us to test our patient for a rasopathy. At the level of the appearance of the three patients, they have strikingly similar and distinctive facial features, which are characterized by the combination of down-slanting palpebral fissures, hypertelorism, a wide mouth with down-turned corners and thin upper lips in the shape of a cupid’s bow (Fig. 1a). Additional overlapping features include large and low-set ears, a bulbous tip of the nose and curly hair. PACS1 is a trans-golgi-membrane traffic regulator that directs protein cargo (3). It is highly expressed in brain during embryonic development and is down regulated in the postnatal period (4). The recurrent variant c.[607C>T];[=], p.[Arg203Trp];[=] is located in close proximity to the CK2-binding motif and therefore possibly influences the binding properties of PACS1 (Fig. 1b). Antisense experiments in zebrafish led to the suggestion that this variant exerts a dominant negative effect by influencing the fate of SOX10-positive neural crest cells, thus creating the facial dysmorphisms (2). However, additional patients and more detailed functional experiments are needed to confirm this hypothesis and establish a genotype–phenotype correlation. Interestingly, despite the application of WES in large cohorts of patients with neurodevelopmental disorders such as ID, autism and epilepsy, neither variants in PACS1 nor in its close family member, PACS2, have been reported in the literature so far. Moreover, microdeletions encompassing PACS1 on 11q13.1 seem to be very rare events. The DECIPHER database lists only one individual carrying a heterozygous deletion of about 1.1 Mb encompassing PACS1 (https://decipher.sanger.ac.uk). The deletion covers additional 45 RefSeq genes, and the patient seems to display a complex pattern of malformations and dysmorphisms characteristic for a contiguous microdeletion syndrome. This individual, therefore, does not add to delineate the phenotype caused by haploinsufficiency of PACS1. In summary, the recurrent variant c.[607C>T];[=], p.[Arg203Trp];[=] in PACS1 causes the ID syndrome MRD17. Here, we report the third patient with MRD17, providing additional evidence that this variant causes a
Letter to the Editor
Table 1. Clinical features of patients carrying a recurrent PACS1 variant
Age at last examination Pregnancy/delivery Neonatal period
Measurements Weight Length Head circumference Urogenital features
Cerebral MRI
Development Free walking First words IQ Behavior Additional findings
Patient 1 (male); Schuurs-Hoeijmakers et al. (2)
Patient 2 (male); Schuurs-Hoeijmakers et al. (2)
Patient from the present report (male)
3 years 6 m Vacuum extraction at term Seizures Intestinal malrotation Resection of the small intestine, short bowel syndrome
19 years C-section at term No problems recorded
3 years C-section at term Hypotonia Poor weight gain Low IgG levels
15 kg (16th centile) 102 cm (50th centile) 49 cm (16th centile) Cryptorchidism Vesico-urethral reflux Streak testis Cavum septum pellucidum
64.5 kg (16th centile) 181 cm (50th centile) 55.1 cm (16th centile) Unilateral cryptorchidism Unilateral hypoplastic scrotum
13.3 kg (10–25th centile) 95 cm (25th centile) 48.5 cm (10th centile) Normal genitalia
Partial agenesis of the vermis Hypoplasia of the cerebellar hemispheres
Not done
2 years 6 m Not reported 53 Friendly, outgoing
2 years 10 m 3 years No formal assessment Friendly
Mild scoliosis Multiple pigmented nevi
Patent ductus arteriosus Atrial septal defect Small ventricular septal defect Chronic constipation
3 years 4 m 3 years 6 m T];[=], p.[Arg203Trp];[=]) is adjacent to the CK2 binding motif (RRKRY200 ).
301
Letter to the Editor c CeGaT
highly recognizable facial phenotype and broadening the phenotypic spectrum of MRD17.
GmbH Tübingen, Germany, and d MVZ genteQ Hamburg, Germany
Supporting Information Additional supporting information may be found in the online version of this article at the publisher’s web-site.
† These
authors contributed equally to this work.
Acknowledgements
References
The authors would like to thank the parents of the boy for supporting this publication. This study makes use of data generated by the DECIPHER Consortium. A complete list of centres that contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from [email protected]. Funding for the project was provided by the Wellcome Trust.
1. Willemsen MH, Kleefstra T. Making headway with genetic diagnostics of intellectual disabilities. Clin Genet 2014: 85: 101–110. 2. Schuurs-Hoeijmakers JH, Oh EC, Vissers LE et al. Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome. Am J Hum Genet 2012: 91: 1122–1127. 3. Youker RT, Shinde U, Day R, Thomas G. At the crossroads of homoeostasis and disease: roles of the PACS proteins in membrane traffic and apoptosis. Biochem J 2009: 421: 1–15. 4. Wan L, Molloy SS, Thomas L et al. PACS-1 defines a novel gene family of cytosolic sorting proteins required for trans-Golgi network localization. Cell 1998: 94: 205–216.
D. Gadzickia,† D. Döckerb,† M. Schubachc M. Menzelc B. Schmorla F. Stellmerd S. Biskupb,c,† D. Bartholdib,† a MVZ Endokrinologikum Hannover Hannover, Germany b Institute of Clinical Genetics Klinikum Stuttgart Stuttgart, Germany
302
Correspondence: Deborah Bartholdi, MD Institute of Clinical Genetics Klinikum Stuttgart Kriegsbergstr. 60-62 D-70174 Stuttgart Germany Tel.: +49 (0)711 278 74001; Fax: +49 (0)711 278 74000; e-mail: [email protected]
