TY - JOUR
T1 - Multi-gene panel sequencing in highly consanguineous families and patients with congenital forms of skeletal dysplasias
AU - Kakar, Naseebullah
AU - Rehman, Fazal ur
AU - Kaur, Ramandeep
AU - Bhavani, Gandham Sri Lakshmi
AU - Goyal, Manisha
AU - Shah, Hitesh
AU - Kaur, Karandeep
AU - Sodhi, Kushaljit Singh
AU - Kubisch, Christian
AU - Borck, Guntram
AU - Panigrahi, Inusha
AU - Girisha, Katta Mohan
AU - Kornak, Uwe
AU - Spielmann, Malte
N1 - Publisher Copyright:
© 2024 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.
PY - 2024/2/20
Y1 - 2024/2/20
N2 - Skeletal dysplasias (SKDs) are a heterogeneous group of more than 750 genetic disorders characterized by abnormal development, growth, and maintenance of bones or cartilage in the human skeleton. SKDs are often caused by variants in early patterning genes and in many cases part of multiple malformation syndromes and occur in combination with non-skeletal phenotypes. The aim of this study was to investigate the underlying genetic cause of congenital SKDs in highly consanguineous Pakistani families, as well as in sporadic and familial SKD cases from India using multigene panel sequencing analysis. Therefore, we performed panel sequencing of 386 bone-related genes in 7 highly consanguineous families from Pakistan and 27 cases from India affected with SKDs. In the highly consanguineous families, we were able to identify the underlying genetic cause in five out of seven families, resulting in a diagnostic yield of 71%. Whereas, in the sporadic and familial SKD cases, we identified 12 causative variants, corresponding to a diagnostic yield of 44%. The genetic heterogeneity in our cohorts was very high and we were able to detect various types of variants, including missense, nonsense, and frameshift variants, across multiple genes known to cause different types of SKDs. In conclusion, panel sequencing proved to be a highly effective way to decipher the genetic basis of SKDs in highly consanguineous families as well as sporadic and or familial cases from South Asia. Furthermore, our findings expand the allelic spectrum of skeletal dysplasias.
AB - Skeletal dysplasias (SKDs) are a heterogeneous group of more than 750 genetic disorders characterized by abnormal development, growth, and maintenance of bones or cartilage in the human skeleton. SKDs are often caused by variants in early patterning genes and in many cases part of multiple malformation syndromes and occur in combination with non-skeletal phenotypes. The aim of this study was to investigate the underlying genetic cause of congenital SKDs in highly consanguineous Pakistani families, as well as in sporadic and familial SKD cases from India using multigene panel sequencing analysis. Therefore, we performed panel sequencing of 386 bone-related genes in 7 highly consanguineous families from Pakistan and 27 cases from India affected with SKDs. In the highly consanguineous families, we were able to identify the underlying genetic cause in five out of seven families, resulting in a diagnostic yield of 71%. Whereas, in the sporadic and familial SKD cases, we identified 12 causative variants, corresponding to a diagnostic yield of 44%. The genetic heterogeneity in our cohorts was very high and we were able to detect various types of variants, including missense, nonsense, and frameshift variants, across multiple genes known to cause different types of SKDs. In conclusion, panel sequencing proved to be a highly effective way to decipher the genetic basis of SKDs in highly consanguineous families as well as sporadic and or familial cases from South Asia. Furthermore, our findings expand the allelic spectrum of skeletal dysplasias.
KW - diagnostic yield
KW - NGS panel sequencing
KW - skeletal dysplasias
KW - spondyloepimetaphyseal dysplasia
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UR - https://www.mendeley.com/catalogue/bbbae975-3dcf-3ba0-b3ce-e8486b945b82/
U2 - 10.1111/cge.14509
DO - 10.1111/cge.14509
M3 - Article
C2 - 38378010
AN - SCOPUS:85186227599
SN - 0009-9163
JO - Clinical Genetics
JF - Clinical Genetics
ER -