BBS5 and INPP5E mutations associated with ciliopathy disorders in families from Pakistan

Abstract

Ciliopathies are a clinically and genetically heterogeneous group of disorders often exhibiting phenotypic overlap and caused by abnormalities in the structure or function of cellular cilia. As such, a precise molecular diagnosis is important for guiding clinical management and genetic counseling. In the present study, two Pakistani families comprising individuals with overlapping clinical features suggestive of a ciliopathy syndrome, including intellectual disability, obesity, congenital retinal dystrophy, and hypogonadism (in males), were investigated clinically and genetically. Whole‐exome sequencing identified the likely causes of disease as a novel homozygous frameshift mutation (NM_152384.2: c.196delA; p.(Arg66Glufs*12); family 1) in BBS5, and a nonsense mutation (NM_019892.5:c.1879C>T; p.Gln627*; family 2) in INPP5E, previously reported in an extended Pakistani family with MORM syndrome. Our findings expand the molecular spectrum associated with BBS5 mutations in Pakistan and provide further supportive evidence that the INPP5E mutation is a common cause of ciliopathy in Northern Pakistan, likely representing a regional founder mutation. This study also highlights the value of genomic studies in Pakistan for families affected by rare heterogeneous developmental disorders and where clinical phenotyping may be limited by geographical and financial constraints. The identification of the spectrum and frequency of disease‐causing variants within this setting enables the development of population‐specific genetic testing strategies targeting variants common to the local population and improving health care outcomes.

Broadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD

“…4b, Mann-Whitney test p-value > 0.05). One extreme example is the p.(Arg621Gln) variant, which has been observed as a homozygote in two non-syndromic and one mildly syndromic IRD cases in this study and recently reported in one subject with JBTS with no retinal degeneration 15 disorders, JBTS 10 and MORM 9 , characterized by severe neurological manifestations and extra-neurological symptoms which may differ both quantitatively and qualitatively in each affected individual, even within the same family 10,12,16,21,34 . Therefore, the mostly non-syndromic patients described in this study are on a milder spectrum of the INPP5E disease.…”

Characterization of the genetic architecture of BMI in infancy and early childhood reveals age-specific effects and implicates pathways involved in Mendelian obesity

“…Six of these seven genes encode proteins participating in the leptin/melanocortin pathway ( LEP, LEPR (3 variants), PCSK1 (two variants), POMC, ADCY3 , and MC4R ) providing compelling support for the importance of this pathway also in normal growth (Supplementary Table 2). The remaining gene, INPP5E , is implicated in MORM Syndrome (OMIM #610156), a ciliopathy presenting early-onset central obesity 25,26 . Apart from MC4R , the associated variants belong to the Transient and Early Rise clusters, showing that mechanisms at play act very early after birth, some of which in a narrow age window.…”

Clinical and genetic heterogeneity of primary ciliopathies (Review)

“…Neurological abnormalities may also include Dandy-Walker malformation (DWM), ventriculomegaly, periventricular nodular heterotopia, hydrocephalus, encephalocele/meningocele, polymicrogyria, absence of the pituitary gland, corpus callosum defects and morphological brainstem abnormalities ( 83 , 89 - 91 ). A wide range of clinical signs may be observed, such as hypotonia, ataxia, developmental delay, intellectual disability (ID), impaired or absent speech, behavioral disturbances such as hyperactivity and aggressiveness, and self-mutilation ( 92 , 93 ).…”