A Rare Arthrogryposis Syndrome with Multiple Anomalies Diagnosed by Whole Exome Sequencing

Audrey Rae Norby; Caitlin Madden Clifford; Deborah Rose Berman

doi:doi:10.11648/j.jgo.20210904.17

| Peer-Reviewed

A Rare Arthrogryposis Syndrome with Multiple Anomalies Diagnosed by Whole Exome Sequencing

Audrey Rae Norby, Caitlin Madden Clifford, Deborah Rose Berman

Published in Journal of Gynecology and Obstetrics (Volume 9, Issue 4)

Received: 24 May 2021 Accepted: 29 June 2021 Published: 31 August 2021

Views: Downloads:

Download PDF

Share This Article

Twitter
Linked In
Facebook

Abstract

A 31-year-old gravida 1 para 0 was referred to our institution following a fetal anatomic survey demonstrating clubbed feet, flexed wrists, and skin edema. Ultrasound evaluation demonstrated these findings in addition to hemivertebrae, short long bones, contractures of the elbows, wrists, knees, and ankles with limited movement at the shoulders and hips. Further, macrocephaly, microphthalmia, low set ears, micrognathia, hepatomegaly, and an omphalocele were noted. Following termination of the pregnancy, whole exome sequencing ultimately identified compound heterozygous mutations in the NEK9 gene. One mutation in our case, c.136G>T, has never been reported; the other, c.1432del, has been reported once. To date, NEK9 mutations have been documented in three families with all affected individuals diagnosed with arthrogryposis. Our patient underwent targeted gene variant testing in two subsequent pregnancies, confirming identification of one of the two familial NEK9 gene mutations each time. Both pregnancies culminated in term deliveries of healthy neonates. This case illustrates a diagnosis of an extremely rare single gene disorder in the pregnancy of a non-consanguineous German couple, providing further evidence toward arthrogryposis with other anomalies as a recessive disease associated with NEK9 gene mutations. Finally, this case demonstrates whole exome sequencing as a valuable adjunct tool for investigating etiology when multiple fetal anomalies are identified without diagnosis on more standard tests.

Published in	Journal of Gynecology and Obstetrics (Volume 9, Issue 4)
DOI	10.11648/j.jgo.20210904.17
Page(s)	128-131
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2024. Published by Science Publishing Group

Keywords

Arthrogryposis, Whole Exome Sequencing, NEK9

References

[1]	Dar PE, Shani H, Evans MI. Cell-free DNA: comparison of technologies. Clinics in Laboratory Medicine. 2016 Mar 18; 36 (2): 199-211.
[2]	Kowalczyk B, Feluś J. Arthrogryposis: an update on clinical aspects, etiology, and treatment strategies. Archives of medical science: AMS. 2016 Feb 1; 12 (1): 10.
[3]	Hall JG. Genetic aspects of arthrogryposis. Clinical orthopaedics and related research. 1985 Apr (194): 44-53.
[4]	Filges I, Tercanli S, Hall JG. Fetal arthrogryposis: Challenges and perspectives for prenatal detection and management. In American Journal of Medical Genetics Part C: Seminars in Medical Genetics 2019 Sep (Vol. 181, No. 3, pp. 327-336). Hoboken, USA: John Wiley & Sons, Inc..
[5]	Mullegama SV, Elsea SH. Clinical and molecular aspects of MBD5-associated neurodevelopmental disorder (MAND). European Journal of Human Genetics. 2016 Sep; 24 (9): 1235-43.
[6]	Jaillard S, Dubourg C, Gérard-Blanluet M, Delahaye A, Pasquier L, Dupont C, Henry C, Tabet AC, Lucas J, Aboura A, David V. 2q23. 1 microdeletion identified by array comparative genomic hybridisation: an emerging phenotype with Angelman-like features?. Journal of medical genetics. 2009 Dec 1; 46 (12): 847-55.
[7]	Talkowski ME, Mullegama SV, Rosenfeld JA, Van Bon BW, Shen Y, Repnikova EA, Gastier-Foster J, Thrush DL, Kathiresan S, Ruderfer DM, Chiang C. Assessment of 2q23. 1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum disorder. The American Journal of human genetics. 2011 Oct 7; 89 (4): 551-63.
[8]	Noh GJ, Graham Jr JM. 2q23. 1 microdeletion of the MBD5 gene in a female with seizures, developmental delay and distinct dysmorphic features. European journal of medical genetics. 2012 May 1; 55 (5): 354-7.
[9]	Van Bon BW, Koolen DA, Brueton L, McMullan D, Lichtenbelt KD, Adès LC, Peters G, Gibson K, Novara F, Pramparo T, Dalla Bernardina B. The 2q23. 1 microdeletion syndrome: clinical and behavioural phenotype. European journal of human genetics. 2010 Feb; 18 (2): 163-70.
[10]	O'regan L, Blot J, Fry AM. Mitotic regulation by NIMA-related kinases. Cell division. 2007 Dec; 2 (1): 1-2.
[11]	Levinsohn JL, Sugarman JL, McNiff JM, Antaya RJ, Choate KA. Somatic mutations in NEK9 cause nevus comedonicus. The American Journal of Human Genetics. 2016 May 5; 98 (5): 1030-7.
[12]	Xu Z, Shen W, Pan A, Sun F, Zhang J, Gao P, Li L. Decreased Nek9 expression correlates with aggressive behaviour and predicts unfavourable prognosis in breast cancer. Pathology. 2020 Apr 1; 52 (3): 329-35.
[13]	Casey JP, Brennan K, Scheidel N, McGettigan P, Lavin PT, Carter S, Ennis S, Dorkins H, Ghali N, Blacque OE, Mc Gee MM. Recessive NEK9 mutation causes a lethal skeletal dysplasia with evidence of cell cycle and ciliary defects. Human molecular genetics. 2016 May 1; 25 (9): 1824-35.
[14]	Alkuraya FS. Arthrogryposis, perthes disease, and upward gaze palsy: a novel autosomal recessive syndromic form of arthrogryposis. American Journal of Medical Genetics Part A. 2011 Feb; 155 (2): 297-300.
[15]	Shaheen R, Patel N, Shamseldin H, Alzahrani F, Al-Yamany R, ALMoisheer A, Ewida N, Anazi S, Alnemer M, Elsheikh M, Alfaleh K. Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort. Genetics in Medicine. 2016 Jul; 18 (7): 686-95.

Cite This Article

Plain Text BibTeX RIS

APA Style

Audrey Rae Norby, Caitlin Madden Clifford, Deborah Rose Berman. (2021). A Rare Arthrogryposis Syndrome with Multiple Anomalies Diagnosed by Whole Exome Sequencing. Journal of Gynecology and Obstetrics, 9(4), 128-131. https://doi.org/10.11648/j.jgo.20210904.17

Copy | Download

ACS Style

Audrey Rae Norby; Caitlin Madden Clifford; Deborah Rose Berman. A Rare Arthrogryposis Syndrome with Multiple Anomalies Diagnosed by Whole Exome Sequencing. J. Gynecol. Obstet. 2021, 9(4), 128-131. doi: 10.11648/j.jgo.20210904.17

Copy | Download

AMA Style

Audrey Rae Norby, Caitlin Madden Clifford, Deborah Rose Berman. A Rare Arthrogryposis Syndrome with Multiple Anomalies Diagnosed by Whole Exome Sequencing. J Gynecol Obstet. 2021;9(4):128-131. doi: 10.11648/j.jgo.20210904.17

Copy | Download

@article{10.11648/j.jgo.20210904.17,
  author = {Audrey Rae Norby and Caitlin Madden Clifford and Deborah Rose Berman},
  title = {A Rare Arthrogryposis Syndrome with Multiple Anomalies Diagnosed by Whole Exome Sequencing},
  journal = {Journal of Gynecology and Obstetrics},
  volume = {9},
  number = {4},
  pages = {128-131},
  doi = {10.11648/j.jgo.20210904.17},
  url = {https://doi.org/10.11648/j.jgo.20210904.17},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.jgo.20210904.17},
  abstract = {A 31-year-old gravida 1 para 0 was referred to our institution following a fetal anatomic survey demonstrating clubbed feet, flexed wrists, and skin edema. Ultrasound evaluation demonstrated these findings in addition to hemivertebrae, short long bones, contractures of the elbows, wrists, knees, and ankles with limited movement at the shoulders and hips. Further, macrocephaly, microphthalmia, low set ears, micrognathia, hepatomegaly, and an omphalocele were noted. Following termination of the pregnancy, whole exome sequencing ultimately identified compound heterozygous mutations in the NEK9 gene. One mutation in our case, c.136G>T, has never been reported; the other, c.1432del, has been reported once. To date, NEK9 mutations have been documented in three families with all affected individuals diagnosed with arthrogryposis. Our patient underwent targeted gene variant testing in two subsequent pregnancies, confirming identification of one of the two familial NEK9 gene mutations each time. Both pregnancies culminated in term deliveries of healthy neonates. This case illustrates a diagnosis of an extremely rare single gene disorder in the pregnancy of a non-consanguineous German couple, providing further evidence toward arthrogryposis with other anomalies as a recessive disease associated with NEK9 gene mutations. Finally, this case demonstrates whole exome sequencing as a valuable adjunct tool for investigating etiology when multiple fetal anomalies are identified without diagnosis on more standard tests.},
 year = {2021}
}

Copy | Download

TY  - JOUR
T1  - A Rare Arthrogryposis Syndrome with Multiple Anomalies Diagnosed by Whole Exome Sequencing
AU  - Audrey Rae Norby
AU  - Caitlin Madden Clifford
AU  - Deborah Rose Berman
Y1  - 2021/08/31
PY  - 2021
N1  - https://doi.org/10.11648/j.jgo.20210904.17
DO  - 10.11648/j.jgo.20210904.17
T2  - Journal of Gynecology and Obstetrics
JF  - Journal of Gynecology and Obstetrics
JO  - Journal of Gynecology and Obstetrics
SP  - 128
EP  - 131
PB  - Science Publishing Group
SN  - 2376-7820
UR  - https://doi.org/10.11648/j.jgo.20210904.17
AB  - A 31-year-old gravida 1 para 0 was referred to our institution following a fetal anatomic survey demonstrating clubbed feet, flexed wrists, and skin edema. Ultrasound evaluation demonstrated these findings in addition to hemivertebrae, short long bones, contractures of the elbows, wrists, knees, and ankles with limited movement at the shoulders and hips. Further, macrocephaly, microphthalmia, low set ears, micrognathia, hepatomegaly, and an omphalocele were noted. Following termination of the pregnancy, whole exome sequencing ultimately identified compound heterozygous mutations in the NEK9 gene. One mutation in our case, c.136G>T, has never been reported; the other, c.1432del, has been reported once. To date, NEK9 mutations have been documented in three families with all affected individuals diagnosed with arthrogryposis. Our patient underwent targeted gene variant testing in two subsequent pregnancies, confirming identification of one of the two familial NEK9 gene mutations each time. Both pregnancies culminated in term deliveries of healthy neonates. This case illustrates a diagnosis of an extremely rare single gene disorder in the pregnancy of a non-consanguineous German couple, providing further evidence toward arthrogryposis with other anomalies as a recessive disease associated with NEK9 gene mutations. Finally, this case demonstrates whole exome sequencing as a valuable adjunct tool for investigating etiology when multiple fetal anomalies are identified without diagnosis on more standard tests.
VL  - 9
IS  - 4
ER  -

Copy | Download

Author Information

Audrey Rae Norby

Department of Maternal Fetal Medicine, Michigan Medicine, Ann Arbor, USA
Caitlin Madden Clifford

Department of Maternal Fetal Medicine, Michigan Medicine, Ann Arbor, USA
Deborah Rose Berman

Department of Maternal Fetal Medicine, Michigan Medicine, Ann Arbor, USA

Download PDF

Sections

Plain Text BibTeX RIS

APA Style

Audrey Rae Norby, Caitlin Madden Clifford, Deborah Rose Berman. (2021). A Rare Arthrogryposis Syndrome with Multiple Anomalies Diagnosed by Whole Exome Sequencing. Journal of Gynecology and Obstetrics, 9(4), 128-131. https://doi.org/10.11648/j.jgo.20210904.17

Copy | Download

ACS Style

Audrey Rae Norby; Caitlin Madden Clifford; Deborah Rose Berman. A Rare Arthrogryposis Syndrome with Multiple Anomalies Diagnosed by Whole Exome Sequencing. J. Gynecol. Obstet. 2021, 9(4), 128-131. doi: 10.11648/j.jgo.20210904.17

Copy | Download

AMA Style

Audrey Rae Norby, Caitlin Madden Clifford, Deborah Rose Berman. A Rare Arthrogryposis Syndrome with Multiple Anomalies Diagnosed by Whole Exome Sequencing. J Gynecol Obstet. 2021;9(4):128-131. doi: 10.11648/j.jgo.20210904.17

Copy | Download

@article{10.11648/j.jgo.20210904.17,
  author = {Audrey Rae Norby and Caitlin Madden Clifford and Deborah Rose Berman},
  title = {A Rare Arthrogryposis Syndrome with Multiple Anomalies Diagnosed by Whole Exome Sequencing},
  journal = {Journal of Gynecology and Obstetrics},
  volume = {9},
  number = {4},
  pages = {128-131},
  doi = {10.11648/j.jgo.20210904.17},
  url = {https://doi.org/10.11648/j.jgo.20210904.17},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.jgo.20210904.17},
  abstract = {A 31-year-old gravida 1 para 0 was referred to our institution following a fetal anatomic survey demonstrating clubbed feet, flexed wrists, and skin edema. Ultrasound evaluation demonstrated these findings in addition to hemivertebrae, short long bones, contractures of the elbows, wrists, knees, and ankles with limited movement at the shoulders and hips. Further, macrocephaly, microphthalmia, low set ears, micrognathia, hepatomegaly, and an omphalocele were noted. Following termination of the pregnancy, whole exome sequencing ultimately identified compound heterozygous mutations in the NEK9 gene. One mutation in our case, c.136G>T, has never been reported; the other, c.1432del, has been reported once. To date, NEK9 mutations have been documented in three families with all affected individuals diagnosed with arthrogryposis. Our patient underwent targeted gene variant testing in two subsequent pregnancies, confirming identification of one of the two familial NEK9 gene mutations each time. Both pregnancies culminated in term deliveries of healthy neonates. This case illustrates a diagnosis of an extremely rare single gene disorder in the pregnancy of a non-consanguineous German couple, providing further evidence toward arthrogryposis with other anomalies as a recessive disease associated with NEK9 gene mutations. Finally, this case demonstrates whole exome sequencing as a valuable adjunct tool for investigating etiology when multiple fetal anomalies are identified without diagnosis on more standard tests.},
 year = {2021}
}

Copy | Download

TY  - JOUR
T1  - A Rare Arthrogryposis Syndrome with Multiple Anomalies Diagnosed by Whole Exome Sequencing
AU  - Audrey Rae Norby
AU  - Caitlin Madden Clifford
AU  - Deborah Rose Berman
Y1  - 2021/08/31
PY  - 2021
N1  - https://doi.org/10.11648/j.jgo.20210904.17
DO  - 10.11648/j.jgo.20210904.17
T2  - Journal of Gynecology and Obstetrics
JF  - Journal of Gynecology and Obstetrics
JO  - Journal of Gynecology and Obstetrics
SP  - 128
EP  - 131
PB  - Science Publishing Group
SN  - 2376-7820
UR  - https://doi.org/10.11648/j.jgo.20210904.17
AB  - A 31-year-old gravida 1 para 0 was referred to our institution following a fetal anatomic survey demonstrating clubbed feet, flexed wrists, and skin edema. Ultrasound evaluation demonstrated these findings in addition to hemivertebrae, short long bones, contractures of the elbows, wrists, knees, and ankles with limited movement at the shoulders and hips. Further, macrocephaly, microphthalmia, low set ears, micrognathia, hepatomegaly, and an omphalocele were noted. Following termination of the pregnancy, whole exome sequencing ultimately identified compound heterozygous mutations in the NEK9 gene. One mutation in our case, c.136G>T, has never been reported; the other, c.1432del, has been reported once. To date, NEK9 mutations have been documented in three families with all affected individuals diagnosed with arthrogryposis. Our patient underwent targeted gene variant testing in two subsequent pregnancies, confirming identification of one of the two familial NEK9 gene mutations each time. Both pregnancies culminated in term deliveries of healthy neonates. This case illustrates a diagnosis of an extremely rare single gene disorder in the pregnancy of a non-consanguineous German couple, providing further evidence toward arthrogryposis with other anomalies as a recessive disease associated with NEK9 gene mutations. Finally, this case demonstrates whole exome sequencing as a valuable adjunct tool for investigating etiology when multiple fetal anomalies are identified without diagnosis on more standard tests.
VL  - 9
IS  - 4
ER  -

Copy | Download