Femoral‐tibial‐digital malformations in a boy with the Japanese founder triplication of BHLHA9

Abstract

TO THE EDITORRecently, we have identified heterozygous tandem duplications/ triplications of an identical 210,050 bp segment harboring BHLHA9 at chromosome band 17p13.3 in 27 of 51 Japanese families with split-hand/foot malformation (SHFM), SHFM with long bone deficiency (SHFLD) that usually affects the tibia, or the Gollop-Wolfgang complex (GWC) characterized by femoral bifurcation, tibial hypoplasia/aplasia, and SHFM [Nagata et al., 2014]. The results provide further support for the involvement of heterozygous copy number gains of BHLHA9 in the development of SHFM and SHFLD [Klopocki et al., 2012;Petit et al., 2014], and indicate for the first time the relevance of BHLHA9 overdosage in the occurrence of GWC. Notably, SHFLD and GWC are more à Correspondence to:

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

“…of families/ individuals with duplication/ triplication ( a )Limb anomalies of affected individualsExtra-limb manifestationsSpecial remarksezirovitz et al, 2008 [3]1 family9 affected individualsSHFM (4), SHFLD [tibial hemimelia] (3), Tibial hemimelia/aplasia only (2)NoAutosomal dominant (AD) inheritance/ Variable expressivity (VE)/, Incomplete penetrance (IP),Defined candidate region to 17p13.1 – 17p13.3; ~ 861 kbArmour et al, 2011 [4]3 families (?1 with triplication a ) with 12 affected individuals7 with duplication: 6 affected, 1 unaffectedSplit hand only (3),SHFLD [tibial hypoplasia/aplasia] (9)NoAD inheritance/ VE/ IPDefined critical region of ~ 173 kb, ? BHLHA9 or AC016292 duplicationKlopocki et al, 2011 [5]17 families (out of 56)82 with duplication: 42 affected, 40 unaffectedSHFLD [tibial hemimelia] (18/31)Only SHFM (5)NoAD inheritance/ VE/ IPSex bias: (Male>Female), affected females with more severe phenotypeDefined critical region of ~ 11.8 kbencompassing only BHLHA9 genePetit et al, 2013 [7]2 affected with duplicationCase 1 SHFLD [R/radial agenesis and hypoplastic R/ulna and L/radial hypoplasia]Case 2 SHFM onlyCase 1 small ASDInvolvement of radius reported for the first timeCurry et al, 2013 [8]1 affected14 families in this report (total of 21 families analyzed) with 17p13.3 duplications that includes BHLHA9 SHFLD [tibial hemimelia]Cleft palate, Mild IDLuk et al, 2014 [9]1 affected fetus a Unaffected mother a both with duplicationSplit handsNoFirst case with prenatal genetic diagnosisPetit et al, 2014 [10]13 families with 42 affected individuals and 19 unaffected obligate carriers;29 with the duplication (20 affected, 9 unaffected)SHFLD (18)NoAD inheritance/ VE/ IPInvolvement of radius in 2 individualsFemur hypoplasia in one patientAffected males with more severe phenotypeAl Kaissi et al, 2014 [11]1 affectedFather- bilateral partial syndactylySHFM, tibial hemimeliaSacral hypoplasia, DD, Thrombocyto-peniaNagata et al, 2014 [12]27 families64 with the duplication/triplication (42/42 affected patients, 22/47 unaffected relatives);2/1000 Japanese controls positive for duplicationSHFM (29), SHFLD (11), GWC (2)NRNo sex biasSHFLD and GWC more common in triplicationsNagata et al, 2015 [13]1 affected child a Unaffected mother a both with triplicationSHFM with tibial aplasia (R)/ hypoplasia (L) and wide R/ distal femoral metaphysis (GWC-like malformation)No…”

“…The first case of SHFM with a prenatal diagnosis of 17p13.3 triplication was reported in 2014 [9]. In the same year, there were two reports describing the molecular genetic basis of SHFLD in two large cohorts of patients from 13 families in France [10] and 51 families in Japan [12]. They reported the rare but possible involvement of the radius and the femur in patients with SHFLD with BHLHA9 duplication or triplication [10, 12].…”

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

“…1 The autosomal dominant SHFLD3 (OMIM [Online Mendelian Inheritance in Man] 612576) is associated with the 17p13.3 duplications/triplications whose breakpoints encompass the transcription factor basic helix-loop-helix family, member A9 (ID: 727857, BHLHA9). [2][3][4][5] Moreover, among different reported clinical data, the deoxyribonucleic acid (DNA) copy number involving BHLHA9 constitutes a strong underling factor with a dosage effect for the development of a range of limb malformations, with variable expressivity and incomplete penetrance. 5 BHLHA9 encodes a putative basic helix-loop-helix DNA-binding protein.…”

“…[2][3][4][5] Moreover, among different reported clinical data, the deoxyribonucleic acid (DNA) copy number involving BHLHA9 constitutes a strong underling factor with a dosage effect for the development of a range of limb malformations, with variable expressivity and incomplete penetrance. 5 BHLHA9 encodes a putative basic helix-loop-helix DNA-binding protein. Knockdown of its ortholog in zebrafish (bhlha9) resulted in shortening of the pectoral fins, 3 while a Bhlha9 knockout mouse model exhibited various degrees of syndactyly in the forelimbs, with an incomplete separation of digits 2 and 3, the index and middle fingers.…”