Incomplete penetrance of autosomal recessive anophthalmia in a large consanguineous family

Background: Keratoconus (KC) is usually bilateral, noninflammatory progressive corneal ectasia in which the cornea becomes progressively thin and conical. Despite the strong evidence of genetic contribution in KC, the etiology of KC is not understood in most cases. Methods: In this study, we used whole-exome sequencing to identify the genetic cause of KC in two sibs in a consanguineous family. The Homozygous frameshift variant NM_001253826.1:c.60delC;p.Leu21Cysfs*6 was identified in the gene Nacetylgalactosaminyltransferase 14 (GALNT14). The variant does not exist in all public databases neither in our internal exome database. Moreover, no database harbours homozygous loss of function variants in the candidate gene. Result: GALNT14 catalyses the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D- galactosamine residue to a serine or threonine residue on target proteins especially Mucins. Conclusion: As alterations of mucin’s glycosylation are linked to a number of eye diseases, we demonstrate in this study an association between the truncated protein GALNT14 and KC.

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Identification of novel locus at chromosome 3p12.3-q13.31 for autosomal recessive intellectual disability in a consanguineous family

Clinical Genetics ◽

10.1111/cge.12161 ◽

2013 ◽

Vol 85 (4) ◽

pp. 390-392

Author(s):

S. Dad ◽

E. Østergaard ◽

K.A. Wadt ◽

J. Lunding ◽

H. Eiberg ◽

...

Keyword(s):

Intellectual Disability ◽

Autosomal Recessive ◽

Consanguineous Family

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Autosomal Recessive Trait of UMOD Gene in Consanguineous Family Presented with End Stage Renal Disease

Journal of Clinical & Experimental Nephrology ◽

10.21767/2472-5056.100072 ◽

2018 ◽

Vol 03 (04) ◽

Cited By ~ 1

Author(s):

Abdulmecit Yildiz ◽

Orhan Gorukmez ◽

Aysegul Oruc ◽

Cuma Bulent Gul ◽

Suat Akgur ◽

...

Keyword(s):

Renal Disease ◽

End Stage Renal Disease ◽

Autosomal Recessive ◽

Recessive Trait ◽

Autosomal Recessive Trait ◽

Consanguineous Family ◽

Stage Renal Disease ◽

End Stage

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A Novel GDAP1 Mutation 439delA is Associated with Autosomal Recessive CMT Disease

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100005199 ◽

2006 ◽

Vol 33 (3) ◽

pp. 311-316 ◽

Cited By ~ 4

Author(s):

Domna-Maria Georgiou ◽

Paschalis Nicolaou ◽

David Chitayat ◽

Pantelitsa Koutsou ◽

Riyana Babul-Hirji ◽

...

Keyword(s):

Autosomal Recessive ◽

Autosomal Dominant ◽

Molecular Genetic ◽

Sensory Neuropathy ◽

Pathogenic Mutation ◽

Chromosome 8 ◽

Consanguineous Family ◽

Single Nucleotide ◽

The Family ◽

Neuropathological Criteria

Background:Charcot-Marie-Tooth (CMT) disease is the most common form of inherited motor and sensory neuropathy. Based on neurophysiological and neuropathological criteria CMT has been sub-classified into two main types: demyelinating and axonal. Furthermore, it is genetically heterogeneous with autosomal dominant, autosomal recessive (AR) and X-linked modes of inheritance. Thus far, seven genes have been identified in association with the demyelinating AR-CMT disease. We hereby report our clinical and molecular genetic findings in a consanguineous family with AR-CMT.Methods:Two young sisters with AR-CMT and other non-affected family members were clinically and electrophysiologically evaluated and then molecular genetic investigation was carried out in order to identify the pathogenic mutation.Results:Following an initial indication for linkage of the family to the CMT4A locus on chromosome 8, we sequenced the Ganglioside-induced differentiation-associated protein 1 (GDAP1) gene and identified a single nucleotide deletion in exon 3 that is associated with AR-CMT in the family.Conclusion:We identified a novel GDAP1 439delA mutation that is associated with AR-CMT in a consanguineous family of Iranian descent with two affected young girls and a history in other members of the family.

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A novel in-frame deletion in ZMPSTE24 is associated with autosomal recessive acrogeria (Gottron type) in an extended consanguineous family

Clinical Dysmorphology ◽

10.1097/mcd.0000000000000220 ◽

2018 ◽

Vol 27 (3) ◽

pp. 88-90

Author(s):

Reza Maroofian ◽

Michela Murdocca ◽

Hossein Rezaei-Delui ◽

Amirhossein Nekooei ◽

Majid Mojarad ◽

...

Keyword(s):

Autosomal Recessive ◽

Consanguineous Family

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A homozygous mutation in a consanguineous family consolidates the role ofALDH1A3in autosomal recessive microphthalmia

Clinical Genetics ◽

10.1111/cge.12277 ◽

2013 ◽

Vol 86 (3) ◽

pp. 276-281 ◽

Cited By ~ 16

Author(s):

L. Roos ◽

M. Fang ◽

C. Dali ◽

H. Jensen ◽

N. Christoffersen ◽

...

Keyword(s):

Autosomal Recessive ◽

Homozygous Mutation ◽

Consanguineous Family

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Bardet-Biedl syndrome due to a pathogenic mutation on CEP290 and an unreported TTC8 variant

10.33118/oaj.rep.2019.01.001 ◽

2018 ◽

Author(s):

Samantha Karlin

Keyword(s):

Autosomal Recessive ◽

Pathogenic Mutation ◽

Incomplete Penetrance ◽

Male Hypogonadism ◽

Current Management ◽

Bardet Biedl Syndrome ◽

Excessive Weight ◽

Mutation Database ◽

Heterozygous Variant ◽

Its Gene

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive or triallelic ciliopathy disorder characterized by obesity, male hypogonadism, renal impairment, polydactyly, and intellectual disability. We present a case report of an African-American male with excessive weight gain and prediabetes who was referred to Genetics at 2½ years of age. Physical exam findings included obesity, macrocephaly, bilateral macrotia, brachydactyly, and small genitalia. Gene sequencing identified two mutations highly suggestive of BBS: a heterozygous variant in the CEP290 gene (c.4393 C>T) and a heterozygous variant in the TTC8 gene (c.1021 C>T). Twenty-one genes have been associated with the 21 types of BBS to date, all demonstrating variable expressivity and incomplete penetrance. There is no cure for BBS, and current management focuses on preventing and treating symptoms. CEP290 mutations are associated with BBS type 14, and only 1% of affected individuals carry a mutation on this gene. TTC8 mutations are associated with BBS type 8, and its gene frequency is also 1% in individuals with BBS. The TTC8 variant found in our propositus (p.Arg341Trp) has not been previously reported in the Human Gene Mutation Database. In this variant, tryptophan replaces the normal arginine at position 341 of the TTC8 protein. To our knowledge, this is the first report linking this specific TTC8 variant with BBS. Keywords: Bardet-Biedl Syndrome, Ciliopathy disorder, Childhood obesity, Genetic obesity, CEP290, TTC8

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Rare autosomal recessive spastic paraplegias

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2019.11.26-35 ◽

2019 ◽

pp. 26-35

Author(s):

Г.Е. Руденская ◽

В.А. Кадникова ◽

А.Л. Чухрова ◽

Т.В. Маркова ◽

О.П. Рыжкова

Keyword(s):

Autosomal Recessive ◽

Clinical Investigation ◽

Wide Spectrum ◽

Spastic Paraparesis ◽

Bioinformatic Analysis ◽

Homozygous Mutation ◽

Consanguineous Family ◽

Behavioral Impairment ◽

Dna Diagnostics ◽

Complex Investigation

Актуальность. Наследственные спастические параплегии (НСП) - одна из наиболее гетерогенных групп наследственных нервных болезней, насчитывающая около 80 клинико-генетических форм (SPG) с хронологической нумерацией. Методы высокопроизводительного экзомного секвенирования (MPS) принципиально расширили возможности выделения новых SPG и практической ДНК-диагностики. В ФГБНУ МГНЦ проводится первое в России комплексное клинико-молекулярное исследование НСП на основе MPS и ряда дополнительных методов ДНК-анализа. Группа верифицированных случаев насчитывает 114 семей с 20 различными формами, включая редкие аутосомно-рецессивные (АР) формы, мало известные генетикам и неврологам. Цель: представить первые российские наблюдения редких АР форм: SPG5, SPG26, SPG35 и SPG39, связанных соответственно с генами CYP7B1, B4GALNT1, FA2H и PNPLA6, участвующими в разных звеньях липидного обмена. Методы. Первичная группа включала около 200 российских семей с предварительным клиническим диагнозом НСП или сходных болезней; основная группа: 114 семей с диагностированной формой SPG; материал статьи: 4 семьи. Использованы методы: клинико-генеалогический, кастомная MPS-панель «параплегии» (64 гена); секвенирование по Сэнгеру; мультиплексная-лигаза зависимая амплификация MLPA (выборочно); полноэкзомное секвенирование WES (выборочно); биоинформатический анализ. Результаты: подгруппа АР SPG включила 22 семьи/12 форм. Представленные 4 формы выявлены в единичных семьях. SPG5: подросток 17 лет в русской семье; начало в 15 лет, умеренный спастический парапарез, легкая сопутствующая атаксия. Генотип CYP7B1: ранее описанные мутации с.334С>T (p.Arg112Ter)/c.1190C>T (p.Pro397Leu) у больного и здоровой сестры 8 лет (доклиническая стадия), родители - гетерозиготные носители. SPG26: мальчик 13 лет в неинбредной русской семье; начало в раннем детстве, медленно прогрессирующий спастический парапарез, дизартрия, когнитивные и поведенческие нарушения, нормальная МРТ. Генотип B4GALNT1: новая мутация c.1514G>C (p.Arg505Pro) в гомозиготном состоянии у больного, в гетерозиготном - у родителей. Случай SPG26 - 14-й описанный в мире, гомозиготность по мутации, вызывающей очень редкую форму SPG, в неинбредной русской семье необычна. SPG35: мальчик 5 лет в этнически смешанной семье (мать русская, отец татарско-бурятского происхождения) из Сибири; начало в 4 года, быстро прогрессирующий спастический парапарез без других симптомов, нормальная МРТ. Генотип FA2H: ранее описанная мутация с.805С>T (p.Arg269Cys) и новая мутация c.106C>T (p.Leu36Phe). SPG39: мальчик 10 лет в русско-татарской семье; начало в 5 лет, умеренный спастический парапарез без других симптомов. Генотип PNPLA6: описанная ранее интронная мутация с.199-2A>T / новая мутация c.2033G>A (p.Gly678Asp), родители - гетерозиготные носители. Выводы. НСП у российских больных представлены широким спектром клинико-генетических форм, включая редкие АР SPG в неинбредных русских и в этнически смешанных семьях. Cлучаи SPG5, SPG26, SPG35 и SPG39 - первые российские описания. Из найденных в 4 генах 7 мутаций три ранее не описаны. MPS - метод выбора ДНК-диагностики болезней с выраженной генетической гетерогенностью, таких, как НСП. Objective: hereditary spastic paraplegias (HSP) are a heterogeneous group including about 80 forms: SPGs (Spastic Paraplegia Gene) numbered chronologically. Massive parallel sequencing MPS greatly improved possibilities of new SPGs disclosure and of practical DNA diagnostics. First Russian HSP complex investigation of HSP using MPS is being performed in FSBI PCMG. By now, the group of genetically diagnosed cases numbers 114 families with 20 different SPGs, including rare autosomal recessive forms poorly known to geneticists and neurologists. Aim: to present first Russian cases of rare autosomal recessive (AR) forms: SPG5, SPG26, SPG35, and SPG39. The genes, CYP7B1, B4GALNT1, FA2H, and FA2H correspondingly, are involved in lipid metabolism. Materials: initial group: about 200 Russian families with preliminary clinical diagnosis of HSP or alike disorders; index group: 114 SPG-confirmed families; paper material: the four families. Methods: clinical investigation, genealogical analysis; molecular methods: custom MPS-panel “paraplegias” (63 genes), Sanger sequencing, multiplex ligation-dependent probe amplification MLPA (selectively), whole-exome sequencing WES (selectively); bioinformatic analysis. Results. Subgroup of AR SPG included 22 families/12 forms. SPG5, 26, 35, 39 were detected in single families. SPG5: a 17-year-old youth in a Russian family; onset in 15 years, moderate spastic paraparesis, mild ataxia; CYP7B1 genotype: two earlier reported mutations .334С>T (p.Arg112Ter) и c.1190C>T (p.Pro397Leu) in the patient and in unaffected younger sister (preclinical stage), parents - heterozygous carries. SPG26: a 13-year old boy in a Russian non-consanguineous family; early-childhood onset, slowly progressing paraparesis, dysarthria, cognitive and behavioral impairment; B4GALNT1 genotype: novel homozygous mutation c.1514G>C (p.Arg505Pro) in the boy, heterozygosity in parents; homozygosity for a very rare gene (14th SPG26 world case) in a Russian non-consanguineous family is unusual. SPG35: a 5-year-old boy in a Sibirian ethnically mixed family (Russian mother, father of Tatar-Buryat ethnicity); onset in 4 years, rapidly progressing paraparesis with no other signs, normal MRI; FA2H genotype: reported earlier с.805С>T (p.Arg269Cys) / novel c.106C>T (p.Leu36Phe). SPG39: a 10-year-old boy in a Russian-Tatar family; onset in 5 years, slowly progressing paraparesis with no other signs; PNPLA6 genotype: reported earlier intronic с.199-2A>T novel c.2033G>A (p.Gly678Asp), parents - heterozygous carriers. Conclusions. HSP in Russian patients present a wide spectrum including rare AR SPG in non-consanguineous Russian families and in families of mixed ethnicity. Our SPG5, SPG26, SPG35 and SPG39 cases are first in Russia; of 7 mutations detected in the 4 genes 3 mutations were novel. MPS is method of choice in DNA diagnostics of heterogeneous disorders like HSP.

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