Overlap of polymicrogyria, hydrocephalus, and Joubert syndrome in a family with novel truncating mutations in ADGRG1/GPR56 and KIAA0556

Cauley, Edmund; Hamed, Ahlam A.; Mohamed, Inaam N.; Elseed, Maha A.; Martinez, Samantha; Abozar, Fatima; Abubakr, Rayan; Koko, Mahmoud; Elsayed, Liena; Piao, Xiangshu; Salih, Mustafa A.; Manzini, M. Chiara

doi:10.1007/s10048-019-00577-2

Cited by 19 publications

(24 citation statements)

References 41 publications

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“…In family F79, two predicted pathogenic variants, variants NM_004667.4 (HERC2):c.10855C > T and NM_021949.3(ATP2B3):c.2086C > T, segregated with the disease. In a previous study we reported Sudanese sibling patients each manifesting two independent inherited neurological disorders (Cauley et al, 2019). We rebutted the possibility of two independent disorders in patient F79-568 because a mutation in ATP2B3 was reported in a single study to cause congenital cerebellar ataxia and our patient did not manifest signs of cerebellar involvement (Zanni et al, 2012).…”

Section: Discussionmentioning

confidence: 58%

Exome Sequencing Revealed Mutations in ADAT3 and HERC2 Genes in two Sudanese Families with Syndromic Mental Retardation

Bakhiet

Hamed

Abozar

et al. 2020

Preprint

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BackgroundAutosomal recessive intellectual disabilities, syndromic and non-syndromic, are of specific importance in consanguineous communities. High throughput sequencing technologies have enhanced diagnosing the Mendelian forms of intellectual disability. Mental retardation 36 and 38 are emerging clinical entities with variable presentations that extend beyond adaptive and intellectual functioning. MethodsWe used exome sequencing, bioinformatic tools and Sanger sequencing to diagnose two Sudanese families with syndromic intellectual disability. ResultsWe identified the variant NM_138422.3 (ADAT3):c.430G>A (rs730882213) in a homozygous state in two female siblings manifesting a clinical phenotype consistent with mental retardation 36. This variant was previously identified as pathogenic founder variant in multiple families from the Middle East manifesting mental retardation 36. Our patients had bullet-shaped distal phalanges, expanding the previously reported presentation. In a second family, the proband had a clinical phenotype consistent with mental retardation 38. Genetic analysis revealed the novel homozygous variant NM_004667.4 (HERC2):c.10855C>T as the potential culprit. In addition to what has been reported previously, the proband had cleft lip and palate, bulbous nose, spastic lower limbs and stones in his gallbladder.Conclusion Herein, we corroborated and extended the previously reported phenotypic spectrums associated with autosomal recessive mental retardation 36 and 38.

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Section: Discussionmentioning

confidence: 58%

Exome Sequencing Revealed Mutations in ADAT3 and HERC2 Genes in two Sudanese Families with Syndromic Mental Retardation

Bakhiet

Hamed

Abozar

et al. 2020

Preprint

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“…Joubert syndrome is caused by a large repertoire of biallelic variants affecting genes encoding proteins of the primary cilium. Based on the wide inter-and intra-familial phenotypic variability observed in this disorder, the existence of an oligogenic contribution and/or the occurrence of a genetic modifier (GM) effects have been hypothesed [4][5][6][7][8], which has been subsequently confirmed by a recent clinical report [16]. Here, we identify homozygous variants in KIF7 and KIAA0556 as the molecular events contributing to a variegated JBTS phenotype associated with clinically relevant endocrine abnormalities.…”

Section: Discussionmentioning

confidence: 59%

“…Brain abnormalities including thin corpus callosum and MTS had been also documented by MRI scan [21]. The third family had recently been reported by Cauley et al [16]; remarkably, the affected subjects from consanguineous parents showed the co-inheritance of a frameshift KIAA0556 mutation and a nonsense variant in a polymicrogyriaassociated gene, ADGRG1. They display central nervous system malformations including diffuse polymicrogyria, lissencephaly and cerebellar vermis, pons, and brain stem hypoplasia, and MTS.…”

Section: Discussionmentioning

confidence: 86%

“…Biallelic mutations in KIAA0556 have rarely been reported thus far. To our knowledge, only 4 families with biallelic truncating variants in this gene have been identified and the associated clinical phenotype resembled a form of JBTS spectrum with variable brain malformations including pituitary malformations (Joubert syndrome type 26, JBTS26) [15,16,21,22] (Tables 1 and 2). The first family with three affected subjects of Saudi Arabian origin was described by Sanders et al [15].…”

Section: Discussionmentioning

confidence: 99%

“…They display central nervous system malformations including diffuse polymicrogyria, lissencephaly and cerebellar vermis, pons, and brain stem hypoplasia, and MTS. This clinical complexity was explained by the additive effect of the two truncating mutations [16]. [15].…”

Section: Discussionmentioning

confidence: 99%

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Co-occurrence of mutations in KIF7 and KIAA0556 in Joubert syndrome with ocular coloboma, pituitary malformation and growth hormone deficiency: a case report and literature review

et al. 2020

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Background: Joubert syndrome is a recessive neurodevelopmental disorder characterized by clinical and genetic heterogeneity. Clinical hallmarks include hypotonia, ataxia, facial dysmorphism, abnormal eye movement, irregular breathing pattern cognitive impairment and, the molar tooth sign is the pathognomonic midbrain-hindbrain malformation on magnetic resonance imaging. The disorder is predominantly caused by biallelic mutations in more than 30 genes encoding proteins with a pivotal role in morphology and function of the primary cilium. Oligogenic inheritance or occurrence of genetic modifiers has been suggested to contribute to the variability of the clinical phenotype. We report on a family with peculiar clinical spectrum Joubert syndrome molecularly and clinically dissecting a complex phenotype, in which hypogonadism, pituitary malformation and growth hormone deficiency occur as major features. Case presentation: A 7 year-old male was enrolled in a dedicated "Undiagnosed Patients Program" for a peculiar form of Joubert syndrome complicated by iris and retinochoroidal coloboma, hypogonadism pituitary malformation, and growth hormone deficiency. The molecular basis of the complex phenotype was investigated by whole exome sequencing. The concomitant occurrence of homozygosity for mutations in KIF7 and KIAA0556 was identified, and the assessment of major clinical features associated with mutations in these two genes provided evidence that these two independent events represent the cause underlying the complexity of the present clinical phenotype. Conclusion: Beside the clinical variability of Joubert syndrome, co-occurrence of mutations in ciliopathy-associated genes may contribute to increase the clinical complexity of the trait.

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Katnip is needed to maintain microtubule function and lysosomal delivery to autophagosomes and phagosomes

Starling

Phillips

Ganesh

et al. 2023

MBoC

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The efficient delivery of lysosomes is essential for many cell functions, such as the degradation of unwanted intracellular components by autophagy and the killing and digestion of extracellular microbes within phagosomes. Using the amoeba Dictyostelium discoideum we find that cells lacking Katnip (Katanin interacting protein) have a general defect in lysosomal delivery and although they make autophagosomes and phagosomes correctly, cells are then unable to digest them. Katnip is largely unstudied yet highly conserved across evolution. Previously studies found Katnip mutations in animals cause defects in cilia structure. Here we show that Katnip plays a more general role in maintaining microtubule function. We find that loss of Katnip has no overall effect on microtubule dynamics or organisation, but is important for the transport and degradation of endocytic cargos. Strikingly, Katnip mutants become highly sensitive to GFP-tubulin expression, which leads to microtubule tangles, defective anaphase extension and slow cell growth. Our findings establish a general role for Katnip in regulating microtubule function, beyond the previous roles described in cilia. We speculate this is via a key function in microtubule repair, required to maintain endosomal trafficking and lysosomal degradation. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text]

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Overlap of polymicrogyria, hydrocephalus, and Joubert syndrome in a family with novel truncating mutations in ADGRG1/GPR56 and KIAA0556

Cited by 19 publications

References 41 publications

Exome Sequencing Revealed Mutations in ADAT3 and HERC2 Genes in two Sudanese Families with Syndromic Mental Retardation

Exome Sequencing Revealed Mutations in ADAT3 and HERC2 Genes in two Sudanese Families with Syndromic Mental Retardation

Co-occurrence of mutations in KIF7 and KIAA0556 in Joubert syndrome with ocular coloboma, pituitary malformation and growth hormone deficiency: a case report and literature review

Katnip is needed to maintain microtubule function and lysosomal delivery to autophagosomes and phagosomes

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