A New Split Hand/Foot Malformation with Long Bone Deficiency Familial Case

Fusco, Carmela; Nittis, Pasquelena De; Alfaiz, Ali Abdullah; Pellico, Maria Teresa; Augello, Bartolomeo; Malerba, Natascia; Zelante, Leopoldo; Reymond, Alexandre; Merla, Giuseppe

doi:10.1055/s-0036-1588029

Cited by 4 publications

(1 citation statement)

References 15 publications

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“…The lack of penetrance of reported here 17p13.3 triplication/ duplication is intriguing. However, lack of 17p13.3 duplication penetrance is a well known phenomenon that was described in all reported so far families [ 5 , 17 – 19 ]. One could suspect the presence of additional loci, which modify the SHFLD3 phenotype or block its expression in asymptomatic carriers.…”

Section: Discussionmentioning

confidence: 99%

SHFLD3 phenotypes caused by 17p13.3 triplication/ duplication encompassing Fingerin (BHLHA9) invariably

Bukowska‐Olech

Sowińska‐Seidler

Wierzba

et al. 2022

Orphanet J Rare Dis

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Background Split-hand/ foot malformation with long bone deficiency 3 (SHFLD3) is an extremely rare condition associated with duplications located on 17p13.3, which invariably encompasses the BHLHA9 gene. The disease inherits with variable expressivity and significant incomplete penetrance as high as 50%. Results We have detected 17p13.3 locus one-allele triplication in a male proband from family 1 (F1.1), and duplication in a male proband from family 2 (F2.1) applying array comparative genomic hybridization (array CGH). The rearrangements mapped to the following chromosomal regions–arr[GRCh38] 17p13.3(960254–1291856)×4 in F1.1 and arr[GRCh38] 17p13.3(1227482–1302716)×3 in F2.1. The targeted quantitative PCR revealed that the 17p13.3 locus was also duplicated in the second affected member from family 2 (F2.2; brother of F2.1). In the next step, we performed segregation studies using quantitative PCR and revealed that F1.1 inherited the triplication from his healthy father—F1.2, whereas the locus was unremarkable in the mother of F2.1 & F2.2 and the healthy son of F2.1. However, the duplication was present in a healthy daughter of F2.2, an asymptomatic carrier. The breakpoint analysis allowed to define the exact size and span of the duplicated region in Family 2, i.e., 78,948 bp chr17:1225063–1304010 (HG38). Interestingly, all symptomatic carriers from both families presented with variable SHFLD3 phenotype. The involvement of secondary modifying locus could not be excluded, however, the Sanger sequencing screening of BHLHA9 entire coding sequence was unremarkable for both families. Conclusions We have shed light on the one-allele CNV triplication occurrence that should be considered when a higher probe (over duplication range) signal is noted. Second, all SHFLD3 patients were accurately described regarding infrequent limb phenotypes, which were highly variable even when familial. Of note, all symptomatic individuals were males. SHFLD3 still remains a mysterious ultra-rare disease and our findings do not answer crucial questions regarding the disease low penetrance, variable expression and heterogeneity. However, we have presented some clinical and molecular aspects that may be helpful in daily diagnostic routine, both dysmorphological and molecular assessment, of patients affected with SHFLD3.

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Section: Discussionmentioning

confidence: 99%

SHFLD3 phenotypes caused by 17p13.3 triplication/ duplication encompassing Fingerin (BHLHA9) invariably

Bukowska‐Olech

Sowińska‐Seidler

Wierzba

et al. 2022

Orphanet J Rare Dis

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The role of ultrasound and genetic counsel in prenatal diagnosis of split hand/foot malformation with long bone deficiency

Kucińska‐Chahwan

Szczęśniak

Nowakowska³

et al. 2019

Taiwanese Journal of Obstetrics and Gynecology

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Split hand/foot malformation with long bone deficiency associated with BHLHA9 gene duplication: a case report and review of literature

Paththinige

Sirisena

Escande³

et al. 2019

BMC Med Genet

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Background Split hand/foot malformation (SHFM) is a group of congenital skeletal disorders which may occur either as an isolated abnormality or in syndromic forms with extra-limb manifestations. Chromosomal micro-duplication or micro-triplication involving 17p13.3 region has been described as the most common cause of split hand/foot malformation with long bone deficiency (SHFLD) in several different Caucasian and Asian populations. Gene dosage effect of the extra copies of BHLHA9 gene at this locus has been implicated in the pathogenesis of SHFLD. Case presentation The proband was a female child born to non-consanguineous parents. She was referred for genetic evaluation of bilateral asymmetric ectrodactyly involving both hands and right foot along with right tibial hemimelia. The right foot had fixed clubfoot deformity with only 2 toes. The mother had bilateral ectrodactyly involving both hands, but the rest of the upper limbs and both lower limbs were normal. Neither of them had any other congenital malformations or neurodevelopmental abnormalities. Genetic testing for rearrangement of BHLHA9 gene by quantitative polymerase chain reaction confirmed the duplication of the BHLHA9 gene in both the proband and the mother. Conclusions We report the first Sri Lankan family with genetic diagnosis of BHLHA9 duplication causing SHFLD. This report along with the previously reported cases corroborate the possible etiopathogenic role of BHLHA9 gene dosage imbalances in SHFM and SHFLD across different populations.

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A New Split Hand/Foot Malformation with Long Bone Deficiency Familial Case

Cited by 4 publications

References 15 publications

SHFLD3 phenotypes caused by 17p13.3 triplication/ duplication encompassing Fingerin (BHLHA9) invariably

SHFLD3 phenotypes caused by 17p13.3 triplication/ duplication encompassing Fingerin (BHLHA9) invariably

The role of ultrasound and genetic counsel in prenatal diagnosis of split hand/foot malformation with long bone deficiency

Split hand/foot malformation with long bone deficiency associated with BHLHA9 gene duplication: a case report and review of literature

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