Inherited and de novo biallelic pathogenic variants in
            COL11A1
            result in type 2 Stickler syndrome with severe hearing loss

Background: Genetically determined prelingual hearing loss (HL) may occur in an isolated or syndromic form. Objective: The aim of the study was to unravel the genetic cause of medical problems in a 21-year-old woman, whose phenotypic presentation extended beyond Stickler syndrome and included enlarged vestibular aqueduct (EVA) and persistent microhematuria. Methods and Results: After sequencing of clinical exome, a known de novo COL2A1 pathogenic variant (c.1833+1G>A, p.?) causative for Stickler syndrome and one paternally inherited pathogenic change in COL4A5 (c.1871G>A, p.Gly624Asp) causative for X-linked Alport syndrome were found. No pathogenic variants, including those within the SLC26A4 5′ region (Caucasian EVA haplotype), explaining the development of EVA, were identified. Conclusions: The study reveals a multilocus genomic variation in one individual and provides a molecular diagnosis of two HL syndromes that co-occur in the proband independent of each other. For the third entity, EVA, no etiological factor was identified. Our data emphasize the relevance of detailed clinical phenotyping for accurate genotype interpretation. Focus on broadening the phenotypic spectrum of known genetic syndromes may actually obscure patients with multiple molecular diagnoses.

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CNNM2-Related Disorders: Phenotype and Its Severity Were Associated With the Mode of Inheritance

Frontiers in Pediatrics ◽

10.3389/fped.2021.699568 ◽

2021 ◽

Vol 9 ◽

Author(s):

Han Zhang ◽

Ye Wu ◽

Yuwu Jiang

Keyword(s):

De Novo ◽

Serum Magnesium ◽

Brain Magnetic Resonance Imaging ◽

Functional Studies ◽

Pathogenic Variants ◽

Significant Difference ◽

Domain Variations ◽

Type 3

CNNM2 (Cystathionine-β-synthase-pair Domain Divalent Metal Cation Transport Mediator 2) pathogenic variants have been reported to cause hypomagnesemia, epilepsy, and intellectual disability/developmental delay (ID/DD). We identified two new cases with CNNM2 novel de novo pathogenic variants, c.814T>C and c.976G>C. They both presented with infantile-onset epilepsy with DD and hypomagnesemia refractory to magnesium supplementation. To date, 21 cases with CNNM2-related disorders have been reported. We combined all 23 cases to analyze the features of CNNM2-related disorders. The phenotypes can be classified into three types: type 1, autosomal dominant (AD) inherited simple hypomagnesemia; type 2, AD inherited hypomagnesemia with epilepsy and ID/DD; and type 3, autosomal recessive (AR) inherited hypomagnesemia with epilepsy and ID/DD. All five type 1 cases had no epilepsy or ID/DD; they all had hypomagnesemia, and three of them presented with symptoms secondary to hypomagnesemia. Fifteen type 2 patients could have ID/DD and seizures, which can be controlled with antiseizure medications (ASMs); their variations clustered in the DUF21 domain of CNNM2. All three type 3 patients had seizures from 1 to 6 days after birth; the seizures were refractory, and 1/3 had status epilepticus; ID/DD in these AR-inherited cases was more severe than that of AD-inherited cases; they all had abnormalities of brain magnetic resonance imaging (MRI). Except for one patient whose serum magnesium was the lower limit of normal, others had definite hypomagnesemia. Hypomagnesemia could be improved after magnesium supplement but could not return to the normal level. Variations in the CBS2 domain may be related to lower serum magnesium. However, there was no significant difference in the level of serum magnesium among the patients with three different types of CNNM2-related disorders. The severity of different phenotypes was therefore not explained by decreased serum magnesium. We expanded the spectrum of CNNM2 variants and classified the phenotypes of CNNM2-related disorders into three types. We found that DUF21 domain variations were most associated with CNNM2-related central nervous system phenotypes, whereas hypomagnesemia was more pronounced in patients with CBS2 domain variations, and AR-inherited CNNM2-related disorders had the most severe phenotype. These results provide important clues for further functional studies of CNNM2 and provide basic foundations for more accurate genetic counseling.

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Auditory dysfunction in type 2 Stickler Syndrome

European Archives of Oto-Rhino-Laryngology ◽

10.1007/s00405-020-06306-y ◽

2020 ◽

Author(s):

Philip Alexander ◽

Philip Gomersall ◽

Jack Stancel-Lewis ◽

Gregory Scott Fincham ◽

Arabella Poulson ◽

...

Keyword(s):

Hearing Loss ◽

Spatial Information ◽

Self Report ◽

Direct Result ◽

Stickler Syndrome ◽

Hearing Sensitivity ◽

Central Processing ◽

Auditory Dysfunction ◽

The Impact

Abstract Purpose To present the extent and site of lesion of auditory dysfunction in a large cohort of individuals with type 2 Stickler Syndrome. Type 2 Stickler Syndrome results from a mutation in the gene coding for α-1 type XI pro-collagen, which has been identified in the human vitreous, cartilage and the cochlea of the mouse. The condition is characterised by classic ocular abnormalities, auditory dysfunction, osteoarthropathy and oro-facial dysplasia. Methods This is a population study which used a combination of audiometric, tympanometric, and self-report measures on a series of 65 individuals (mean age 29.2 years, range 3–70, female 63.1%) with genetically confirmed type 2 Stickler Syndrome. Results Hearing impairment was identified in at least one ear for 69% of individuals. Analysis against age-matched normative data showed that reduced hearing sensitivity was present across all test frequencies. Sensorineural hearing loss was most common (77% of ears), with conductive (3%), mixed (7%) and no hearing loss (13%), respectively. The proportion of hypermobile tympanic membranes (24%) was less than previously documented in type 1 Stickler Syndrome. When present, this appears to arise as a direct result of collagen abnormalities in the middle ear. Self-report measures of speech and spatial hearing in sound were comparable to a non-syndromic cohort with similar audiometric thresholds. Conclusions Auditory impairment in type 2 Stickler Syndrome is predominantly associated with cochlear hearing loss of varying severities across affected individuals. The impact on hearing thresholds can be seen across the frequency range, suggesting a contribution of defective collagen throughout the cochlea. Self-report questionnaires showed that difficulties understanding speech, and spatial information in sound (such as that used for localisation), were worse than a young, normal-hearing population but comparable to a non-syndromic cohort with similar audiometric thresholds. Therefore, it is likely that hearing loss in type 2 Stickler Syndrome arises in the auditory periphery, without significant central processing deficits.

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Streptococcus suisMeningitis: First Case Reported in Quebec

Canadian Journal of Infectious Diseases ◽

10.1155/1996/354693 ◽

1996 ◽

Vol 7 (5) ◽

pp. 329-331 ◽

Cited By ~ 17

Author(s):

Sophie Michaud ◽

Raymond Duperval ◽

Robert Higgins

Keyword(s):

Hearing Loss ◽

Clinical Manifestation ◽

Streptococcus Suis ◽

Swine Production ◽

Severe Hearing Loss ◽

Occupational Illness ◽

First Case ◽

Swine Workers ◽

Streptococcal Meningitis

Very fewStreptococcus suisinfections in humans have been reported in Canada, although the condition is frequent in pigs. Meningitis, often accompanied by severe hearing loss, is the most common clinical manifestation. The disease is an occupational illness affecting persons in contact with pigs and may be underdiagnosed because of misidentification of the responsible bacterium. Since Quebec is the leading province for swine production in Canada, physicians and microbiologists should be aware of this infection, especially when a streptococcal meningitis is diagnosed in swine workers. The first case ofS suistype 2 meningitis reported in Quebec is described.

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When Familial Hearing Loss Means Genetic Heterogeneity: A Model Case Report

Diagnostics ◽

10.3390/diagnostics11091636 ◽

2021 ◽

Vol 11 (9) ◽

pp. 1636

Author(s):

Camille Cenni ◽

Luke Mansard ◽

Catherine Blanchet ◽

David Baux ◽

Christel Vaché ◽

...

Keyword(s):

Hearing Loss ◽

Case Report ◽

De Novo ◽

Panel Analysis ◽

Adult Onset ◽

Childhood Onset ◽

Model Case ◽

Pathogenic Variants ◽

Whole Exome ◽

Neonatal Thrombocytopenia

We describe a family with both hearing loss (HL) and thrombocytopenia, caused by pathogenic variants in three genes. The proband was a child with neonatal thrombocytopenia, childhood-onset HL, hyper-laxity and severe myopia. The child’s mother (and some of her relatives) presented with moderate thrombocytopenia and adulthood-onset HL. The child’s father (and some of his relatives) presented with adult-onset HL. An HL panel analysis, completed by whole exome sequencing, was performed in this complex family. We identified three pathogenic variants in three different genes: MYH9, MYO7A and ACTG1. The thrombocytopenia in the child and her mother is explained by the MYH9 variant. The post-lingual HL in the paternal branch is explained by the MYO7A variant, absent in the proband, while the congenital HL of the child is explained by a de novo ACTG1 variant. This family, in which HL segregates, illustrates that multiple genetic conditions coexist in individuals and make patient care more complex than expected.

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A novel variant in the PDE4D gene is the cause of Acrodysostosis type 2 in a Lithuanian patient: a case report

BMC Endocrine Disorders ◽

10.1186/s12902-021-00741-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Gunda Petraitytė ◽

Kamilė Šiaurytė ◽

Violeta Mikštienė ◽

Loreta Cimbalistienė ◽

Dovilė Kriaučiūnienė ◽

...

Keyword(s):

De Novo ◽

Bone Dysplasia ◽

Neurological Involvement ◽

Mild Intellectual Disability ◽

Pathogenic Variants ◽

Novel Variant ◽

Hormonal Resistance ◽

Primary Bone ◽

Conserved Region

Abstract Background Acrodysostosis is a rare hereditary disorder described as a primary bone dysplasia with or without hormonal resistance. Pathogenic variants in the PRKAR1A and PDE4D genes are known genetic causes of this condition. The latter gene variants are more frequently identified in patients with midfacial and nasal hypoplasia and neurological involvement. The aim of our study was to analyse and confirm a genetic cause of acrodysostosis in a male patient. Case presentation We report on a 29-year-old Lithuanian man diagnosed with acrodysostosis type 2. The characteristic phenotype includes specific skeletal abnormalities, facial dysostosis, mild intellectual disability and metabolic syndrome. Using patient’s DNA extracted from peripheral blood sample, the novel, likely pathogenic, heterozygous de novo variant NM_001104631.2:c.581G > C was identified in the gene PDE4D via Sanger sequencing. This variant causes amino acid change (NP_001098101.1:p.(Arg194Pro)) in the functionally relevant upstream conserved region 1 domain of PDE4D. Conclusions This report further expands the knowledge of the consequences of missense variants in PDE4D that affect the upstream conserved region 1 regulatory domain and indicates that pathogenic variants of the gene PDE4D play an important role in the pathogenesis mechanism of acrodysostosis type 2 without significant hormonal resistance.

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Recurrent de novo WFS1 pathogenic variants in Chinese sporadic patients with nonsyndromic sensorineural hearing loss

Molecular Genetics & Genomic Medicine ◽

10.1002/mgg3.1367 ◽

2020 ◽

Vol 8 (8) ◽

Author(s):

Jing Guan ◽

Hongyang Wang ◽

Lan Lan ◽

Yusen Wu ◽

Guohui Chen ◽

...

Keyword(s):

Hearing Loss ◽

Sensorineural Hearing Loss ◽

De Novo ◽

Sensorineural Hearing ◽

Pathogenic Variants

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Dominant monoallelic variant in the PAK2 gene causes Knobloch syndrome type 2

10.1101/2020.10.06.328419 ◽

2020 ◽

Author(s):

Stylianos E. Antonarakis ◽

Ales Holoubek ◽

Melivoia Rapti ◽

Jesse Rademaker ◽

Jenny Meylan ◽

...

Keyword(s):

Cell Cycle Progression ◽

Kinase Activity ◽

De Novo ◽

Synonymous Substitution ◽

Kinase Domain ◽

Germline Mosaicism ◽

Knobloch Syndrome ◽

Pathogenic Variants ◽

Cytoskeletal Dynamics

AbstractKnobloch syndrome is an autosomal recessive phenotype mainly characterized by retinal detachment and encephalocele caused by biallelic pathogenic variants in the COL18A1 gene. However, there are patients clinically diagnosed as Knobloch syndrome with unknown molecular etiology not linked to COL18A1. We studied an historical pedigree (published in 1998) designated as KNO2 (Knobloch type 2 syndrome with intellectual disability, autistic behavior, retinal degeneration, encephalocele). Whole exome sequencing of the two affected siblings and the normal parents resulted in the identification of a PAK2 non-synonymous substitution p.(Glu435Lys) as a causative variant. The variant was monoallelic and apparently de novo in both siblings indicating a likely germline mosaicism in one of the parents; the mosaicism however could not be observed after deep sequencing of blood parental DNA. PAK2 encodes a member of a small group of serine/threonine kinases; these P21-activating kinases (PAKs) are essential in signal transduction and cellular regulation (cytoskeletal dynamics, cell motility, death and survival signaling, and cell cycle progression). Structural analysis of the PAK2 p.(Glu435Lys) variant which is located in the kinase domain of the protein predicts a possible compromise in the kinase activity. Functional analysis of the p.(Glu435Lys) PAK2 variant in transfected HEK293T cells results in a partial loss of the kinase activity. PAK2 has been previously suggested as an autism related gene. Our results show that PAK2 induced phenotypic spectrum is broad and not fully understood. We conclude that the KNO2 syndrome in the studied family is dominant and caused by a deleterious variant in the PAK2 gene.

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