Further delineation of Malan syndrome

Priolo, Manuela; Schanze, Denny; Tatton-Brown, Katrin; Mulder, Paul A.; Tenorio, Jair; Kooblall, Kreepa; Acero, I. H.; Alkuraya, Fowzan S.; Arias, Pedro; Bernardini, Laura; Bijlsma, Emilia K.; Cole, Trevor; Coubes, Christine; Dapía, Irene; Davies, Sally; Donato, Nataliya Di; Elçioğlu, Nursel; Fahrner, Jill A.; Foster, Alison; González, Noelia García; Huber, Ilka; Iascone, Maria; Kaiser, Ann Sophie; Kamath, Arveen; Liebelt, Jan; Lynch, Sally Ann; Maas, Saskia M.; Mammì, Corrado; Mathijssen, Inge B.; McKee, Shane; Menke, Leonie A.; Mirzaa, Ghayda; Montgomery, Tara; Neubauer, D.; Neumann, Thomas; Pintomalli, Letizia; Pisanti, Maria Antonietta; Plomp, Astrid S.; Price, Sue; Salter, Claire; Santos‐Simarro, Fernando; Sarda, Pierre; Segovia, Mabel; Shaw‐Smith, Charles; Smithson, Sarah; Suri, Mohnish; Valdez, Rita; Haeringen, Arie van; Hagen, Johanna M. van; Zollino, Marcella; Lapunzina, Pablo; Thakker, Rajesh; Zenker, Martin; Hennekam, Raoul C. M.

doi:10.1002/humu.23563

Cited by 54 publications

(157 citation statements)

References 36 publications

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“…However, ES revealed in both brothers an identical de novo variant in NFIX pointing to MS, which corresponded with their phenotype. The brothers support the notion that although MS belongs to overgrowth syndromes, this feature may not be constant (Priolo et al, ). On the contrary, ID is usually moderate to severe or even profound in MS (as in Patient P1), more severe than in other overgrowth syndromes.…”

Section: Discussionsupporting

confidence: 57%

“…The variant was predicted to be deleterious using multiple tools (PolyPhen‐2 score 0.998 (probably damaging); SIFT score 0 (deleterious); MutationTaster score 0.994 (disease causing); CADD score 31) and was absent from all databases examined (ESP, ExAC, gnomAD, GEEVS). It affected the NFIX region associated with MS (Priolo et al, ), which was compatible with the clinical picture of the brothers, and the variant could be classified as pathogenic according to the ACMG guidelines (Richards et al, ).…”

Section: Resultsmentioning

confidence: 94%

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Parental gonadal but not somatic mosaicism leading to de novo NFIX variants shared by two brothers with Malan syndrome

Hančárová

Havlovičová

Putzová

et al. 2019

American J of Med Genetics Pt A

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The importance of gonadal mosaicism in families with apparently de novo mutations is being increasingly recognized. We report on two affected brothers initially suggestive of X-linked or autosomal recessive inheritance. Malan syndrome due to shared NFIX variants was diagnosed in the brothers using exome sequencing. The boys shared the same paternal but not maternal haplotype around NFIX, and deep amplicon sequencing showed~7% of the variant in paternal sperm but not in paternal blood and saliva. We performed review of previous cases of gonadal mosaicism, which suggests that the phenomenon is not uncommon. Gonadal mosaicism is often not accompanied by somatic mosaicism in tissues routinely used for testing, and if both types of mosaicism are present, the frequency of the variant in sperm is often higher than in somatic cells. In families with shared apparently de novo variants without evidence of parental somatic mosaicism, the transmitting parent may be determined through haplotyping of exome variants. Gonadal mosaicism has important consequences for recurrence risks and should be considered in genetic counseling in families with de novo variants. K E Y W O R D Sde novo recurrence, gonadal mosaicism, Malan syndrome, NFIX, somatic mosaicism

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Section: Discussionsupporting

confidence: 57%

Section: Resultsmentioning

confidence: 94%

Parental gonadal but not somatic mosaicism leading to de novo NFIX variants shared by two brothers with Malan syndrome

Hančárová

Havlovičová

Putzová

et al. 2019

American J of Med Genetics Pt A

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“…NFIX (OMIM * 164005), a member of the nuclear factor I family of transcription factors, is essential for normal brain and skeletal development and Nfix deficiency in mice leads to brain malformations including ventriculomegaly and partial agenesis of the corpus callosum (Driller et al, ; Malan et al, ). To date, together with the present study, 35 patients were described with Malan syndrome phenotype, all of them presenting deletions involving NFIX gene, with variable breakpoints (Auvin et al, ; Bonaglia et al, ; Dolan et al, ; Dong et al, ; Hino‐Fukuyo et al, ; Jezela‐Stanek et al, ; Jorge et al, ; Karmarkar et al, ; Klaassens et al, ; Kuroda et al, ; Lyon et al, ; Lysy et al, ; Malan et al, ; Natiq et al, ; Nimmakayalu et al, ; Priolo et al, ; Shimojima et al, ; Welham et al, ) (Figure ).…”

Section: Discussionmentioning

confidence: 62%

“…The clinical features observed in individuals with deletions of NFIX and a variable number of other genes do not show significant differences in comparison with individuals who present NFIX point mutations. The main difference seems to be related to the frequency of seizures/epilepsy and EEG abnormalities among individuals with microdeletions (Kuroda et al, ; Priolo et al, ), which may be explained by the presence of a contiguous gene disorder. Located 109 kb from NFIX , CACNA1A has been associated with such increased prevalence of seizures (Auvin et al, ; Marangi et al, ; Natiq et al, ; Priolo et al, ).…”

Section: Discussionmentioning

confidence: 99%

Malan syndrome in a patient with 19p13.2p13.12 deletion encompassing NFIX and CACNA1A genes: Case report and review of the literature

Bellucco

Mello

Meloni

et al. 2019

Molec Gen & Gen Med

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BackgroundMalan syndrome is a recently introduced overgrowth disorder described in a limited number of individuals. Haploinsufficiency and also point mutations of NFIX gene have been proposed as its leading causative mechanism, however, due to the limited number of cases and different deletion sizes, genotype/phenotype correlations are still limited.MethodsHere, we report the first Brazilian case of Malan syndrome caused by a 990 kb deletion in 19p13.2p13.12, focusing on clinical and behavioral aspects of the syndrome.ResultsThe patient presented with macrocephaly, facial dysmorphisms, hypotonia, developmental delay, moderate thoracolumbar scoliosis, and seizures. The intellectual and behavioral assessments showed severe cognitive, language, and adaptive functions impairments. The 19p deleted region of our patient encompasses NFIX, CACNA1A, which seems to be related to a higher frequency of seizures among individuals with microdeletions in 19p13.2, and 15 other coding genes, including CC2D1A and NACC1, both known to be involved in neurobiological process and pathways.ConclusionDeletions involving NFIX gene should be considered in patients with overgrowth during childhood, macrocephaly, developmental delay, and seizures, as well as severe intellectual disability.

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“…Patients with clinical symptoms highly similar to those with Sotos syndrome, but who do not carry mutations to NSD1 , have been shown to carry mutations to other genes, including APC2 and NFIX . Recently, patients carrying haploinsufficient mutations to NFIX were designated as having a clinically distinct syndrome, namely Malan syndrome …”

Section: Introductionmentioning

confidence: 99%

Investigating cortical features of Sotos syndrome using mice heterozygous for Nsd1

Oishi

Zalucki

Vega

et al. 2020

Genes Brain and Behavior

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Sotos syndrome is a developmental disorder characterized by a suite of clinical features. In children, the three cardinal features of Sotos syndrome are a characteristic facial appearance, learning disability and overgrowth (height and/or head circumference > 2 SDs above average). These features are also evident in adults with this syndrome. Over 90% of Sotos syndrome patients are haploinsufficient for the gene encoding nuclear receptor‐binding Su(var)3‐9, Enhancer‐of‐zesteand Trithorax domain‐containing protein 1 (NSD1). NSD1 is a histone methyltransferase that catalyzes the methylation of lysine residue 36 on histone H3. However, although the symptomology of Sotos syndrome is well established, many aspects of NSD1 biology remain unknown. Here, we assessed the expression of Nsd1 within the mouse brain, and showed a predominantly neuronal pattern of expression for this histone‐modifying factor. We also generated a mouse strain lacking one allele of Nsd1 and analyzed morphological and behavioral characteristics in these mice, showing behavioral characteristics reminiscent of some of the deficits seen in Sotos syndrome patients.

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Further delineation of Malan syndrome

Cited by 54 publications

References 36 publications

Parental gonadal but not somatic mosaicism leading to de novo NFIX variants shared by two brothers with Malan syndrome

Parental gonadal but not somatic mosaicism leading to de novo NFIX variants shared by two brothers with Malan syndrome

Malan syndrome in a patient with 19p13.2p13.12 deletion encompassing NFIX and CACNA1A genes: Case report and review of the literature

Investigating cortical features of Sotos syndrome using mice heterozygous for Nsd1

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